Fertility and Sterility - Articles in Press

A tissue-engineered human endometrial stroma that responds to cues for secretory differentiation, decidualization, and menstruation - Corrected Proof

Stacey C. Schutte, Robert N. Taylor — 2012-02-06

Objective: To show the responsiveness of tissue-engineered human endometrial stroma to combinations of hormones that mimic the secretory and menstrual phases of the cycle.Design: In vitro experimental study.Setting: University uterine biology research laboratory.Patient(s): None.Intervention(s): Telomerase immortalized human endometrial stromal cells cultured in monolayers (two-dimensional, 2D) or encapsulated in a collagen I hydrogel (three-dimensional, 3D) to create a simplified tissue-engineered stroma were exposed to hormone treatments mimicking early and late secretory phases, decidualization, and steroid withdrawal conditions to recapitulate menstruation.Main Outcome Measure(s): Morphologic and biochemical markers of decidualization and collagenase activity.Result(s): The 3D tissue can manifest changes in morphology and biochemical markers of decidualization similar to 2D culture and characteristic of endometrial stroma in vivo. Unlike 2D culture, the 3D tissue responded to steroid withdrawal by increased collagenase activity and tissue breakdown.Conclusion(s): Three-dimensional tissue-engineered endometrial stroma can mimic secretory and menstrual phases of the cycle and may be useful for studying uterine receptivity and menstruation in a physiological endocrine environment.

Degradation of actin nucleators affects cortical polarity of aged mouse oocytes - Corrected Proof

2012-02-06

Objective: To investigate the molecular mechanism of mouse oocyte polarity loss during aging.Design: Experimental study.Setting: Academic basic research laboratory.Animal(s): Mice.Intervention(s): Oocytes were collected 16 hours after injection of hCG and cultured in M16 medium for an additional 14 hours with or without caffeine.Main Outcome Measure(s): Expression and localizations of actin nucleators actin-related protein 2/3 complex, JMY, and WAVE2 were examined by immunofluorescence staining, and their messenger RNA levels were examined by real-time reverse transcription–polymerase chain reaction.Result(s): The protein and messenger RNA levels of actin-related protein 2/3 complex, JMY, and WAVE2 were decreased in aged oocytes, but the levels were normal in caffeine-treated aged oocytes.Conclusion(s): Our data indicated that the loss of oocyte polarity may be due to the degradation of actin nucleators in aged oocytes.

Laptop computers with Wi-Fi decreases human sperm motility and increases sperm DNA fragmentation - Corrected Proof

Jean-François Doré, Marie-Christine Chignol — 2012-02-06

We read with interest the article, “Use of laptop computers connected to internet through Wi-Fi decreases human sperm motility and increases sperm DNA fragmentation” by Avendaño et al. . However, we think that the evidence presented in this article cannot support the claim that the observed effects are nonthermal and caused by exposure to a Wi-Fi radiofrequency electromagnetic field.

Reply of the Authors - Corrected Proof

Conrado Avendaño — 2012-02-06

We thank Drs. Doré and Chignol for their interest in and comments on our article . The aim of our study was to evaluate the impact of laptop computers connected to the Internet through Wi-Fi on human sperm. To assess this potential association we used an in vitro model incubating human sperm in the presence of an active portable computer connected to the Internet by Wi-Fi. Doré and Chignol suggest that the sperm damage could have been caused by thermal effects. However, the temperature on each incubation culture medium drop was controlled by an IVF thermometer, and no changes were observed. We have discussed different possible mechanisms responsible for the detrimental effects observed. Decrease of sperm motility and increase in DNA fragmentation may be caused by nonthermal effects, such as lipid peroxidation and reactive oxygen species (ROS) generation .

Growth differentiation factor 3 is induced by bone morphogenetic protein 6 (BMP-6) and BMP-7 and increases luteinizing hormone receptor messenger RNA expression in human granulosa cells - Corrected Proof

2012-02-03

Objective: To examine the relevance of growth differentiation factor 3 (GDF-3) and bone morphogenetic protein (BMP) cytokines in human ovary.Design: Molecular studies.Setting: Research laboratory.Patient(s): Eight women undergoing salpingo-oophorectomy and 30 women undergoing ovarian stimulation for in vitro fertilization.Intervention(s): Localizing GDF-3 protein in human ovaries; granulosa cells (GC) cultured with GDF-3, BMP-6, or BMP-7 followed by RNA extraction.Main Outcome Measure(s): The localization of GDF-3 protein in normal human ovaries via immunohistochemical analysis, GDF-3 messenger RNA (mRNA) expression evaluation via quantitative real-time reverse transcription and polymerase chain reaction (RT-PCR), and evaluation of the effect of GDF-3 on leuteinizing hormone (LH) receptor mRNA expression via quantitative real-time RT-PCR.Result(s): In the ovary, BMP cytokines, of the transforming growth factor beta (TGF-β) superfamily, are known as a luteinization inhibitor by suppressing LH receptor expression in GC. Growth differentiation factor 3, a TGF-β superfamily cytokine, is recognized as an inhibitor of BMP cytokines in other cells. Immunohistochemical analysis showed that GDF-3 was strongly detected in the GC of antral follicles. An in vitro assay revealed that BMP-6 or BMP-7 induced GDF-3 mRNA in GC. Also, GDF-3 increased LH receptor mRNA expression and inhibited the effect of BMP-7, which suppressed the LH receptor mRNA expression in GC.Conclusion(s): GDF-3, induced with BMP-6 and BMP-7, might play a role in folliculogenesis by inhibiting the effect of BMP cytokines.

Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study - Corrected Proof

2012-02-03

Objective: To determine both the negative and positive predictive values of comprehensive chromosome screening (CCS) results for clinical outcome.Design: Data obtained from two prospective, double-blinded, nonselection studies.Setting: Academic center for reproductive medicine.Patient(s): One hundred forty-six couples with a mean maternal age of 34.0 ± 4.4 years and a mean paternal age of 37.3 ± 5.8 years.Intervention(s): Embryo biopsy for DNA fingerprinting and aneuploidy assessment.Main Outcome Measure(s): Failure rate of embryos predicted aneuploid by CCS (negative predictive value) and success rate of embryos predicted euploid by CCS (positive predictive value).Result(s): A total of 255 IVF-derived human embryos were cultured and selected for transfer without influence from CCS analysis. Embryos were biopsied before transfer, including 113 blastomeres at the cleavage stage and 142 trophectoderm biopsies at the blastocyst stage. Comprehensive chromosome screening was highly predictive of clinical outcome, with 96% of aneuploid predicted embryos failing to sustain implantation and 41% sustained implantation from embryos predicted to be euploid.Conclusion(s): These nonselection data provide the first prospective, blinded, clinical study directly measuring the predictive value of aneuploidy screening for clinical outcome. The clinical error rate of an aneuploidy designation is very low (4%), whereas implantation and delivery rates of euploid embryos are increased relative to the entire cohort of transferred embryos.

Glutathione peroxidase activity in seminal plasma and its relationship with classical sperm parameters and in vitro fertilization-intracytoplasmic sperm injection outcome - Corrected Proof

2012-02-01

Objective: To relate the glutathione peroxidase (GPX) activity level in human seminal plasma with standard semen parameters and spermatozoa fertilization potential in terms of fertilization and pregnancy rates in an IVF program.Design: Prospective study.Setting: Human Reproduction Unit at Cruces Hospital (Vizcaya, Spain).Patient(s): Three hundred consecutive males from infertile couples participating in the IVF program.Intervention(s): None.Main Outcome Measure(s): Analysis of GPX activity in seminal plasma by spectrophotometry.Result(s): GPX activity in seminal plasma was significantly lower in patients with abnormal sperm as assessed by 1999 and 2010 World Health Organization (WHO) criteria, compared with normozoospermic individuals. There was a more significant decrease in those samples with severe sperm pathologies. GPX values were significantly lower in samples with severe asthenozoospermia, oligozoospermia, and teratozoospermia compared with normal samples. However, there was no correlation between GPX activity in seminal plasma in IVF patients and fertilization rates or pregnancy outcome.Conclusion(s): Although seminal plasma GPX activity was related to semen quality according to WHO parameters, such an association was not found with IVF–intracytoplasmic sperm injection (ICSI) outcome, presumably because of the well-known ability of IVF-ICSI procedures to overcome sperm deficiencies in the fertilization process.

Committee opinion: role of tubal surgery in the era of assisted reproductive technology - Corrected Proof

The Practice Committee of the American Society for Reproductive Medicine — 2012-01-30

There is a need to determine the optimal treatment methods for patients with tubal factor infertility. This document reviews the available treatments and discusses factors that must be considered when deciding between surgical repair versus in vitro fertilization. This document replaces the 2008 document of the same name.

In vitro effect of unacylated ghrelin and obestatin on human luteal cell function - Corrected Proof

2012-01-30

Objective: To evaluate whether unacylated ghrelin and obestatin were able to influence human luteal cell function. The effect of these two ghrelin-related peptides on progesterone (P4), prostaglandin (PG) F2α, PGE2, and vascular endothelial growth factor (VEGF) release and on VEGF expression in isolated human steroidogenic cells has been investigated.Design: Prospective laboratory study.Setting: University hospital.Patient(s): Corpora lutea were obtained from 23 normally menstruating patients in the midluteal phase of the menstrual cycle.Intervention(s): Human luteal cells were isolated from corpora lutea, and primary cultures were established.Main Outcome Measure(s): P4 and PGs release was assayed by enzyme immunoassay, VEGF secretion by ELISA, and VEGF mRNA expression by real-time polymerase chain reaction.Result(s): P4 and VEGF release were significantly reduced by both unacylated ghrelin and obestatin. Moreover, the highest concentration of obestatin was able to reduce the release of PGE2 and PGF2α. VEGF mRNA expression was not affected by the incubation with any of these ghrelin-related peptides. As expected, CoCl2 was able to induce VEGF release and mRNA expression in luteal cells.Conclusion(s): Our results suggest that, similar to ghrelin, both unacylated ghrelin and obestatin might play a role in regulating the luteal cell function that affects both luteal steroidogenesis and luteotrophic/luteolytic imbalance. These results further underline the pivotal correlation between the ghrelin system and reproduction.

Can FSH co-trigger prevent OHSS? - Corrected Proof

Mitchell P. Rosen, David R. Meldrum — 2012-01-30

FSH co-trigger after ovarian stimulation has been shown to improve oocyte competence and a recent report suggested that the FSH co-trigger can completely prevent OHSS. We report two cases of late OHSS after the FSH co-trigger was administered, underscoring the need for further research on the mechanisms, effects, benefits, and potential risks of FSH co-trigger.

Interim analysis in clinical trials - Corrected Proof

Hui-Chun Su, Mary D. Sammel — 2012-01-30

Mansour and colleagues report a positive effect of intrauterine injections of human chorionic gonadotropin (hCG) on implantation and clinical pregnancy rates (CPR) after in vitro fertilization with intracytoplasmic sperm injection . We congratulate the authors for exploring this intervention in considerable detail. We wish to comment on the interim analyses conducted in this randomized controlled trial and the completeness of their registration at clinicaltrials.gov.

Reply of the Authors - Corrected Proof

Ragaa Mansour — 2012-01-30

We read with interest the Letter by Su and Sammel and wish to respond to their comments. We also wish to thank them for congratulating the investigators for exploring the intervention of intrauterine injection of human chorionic gonadotrophin (hCG) before embryo transfer (ET) .

Remarks from the Editor - Corrected Proof

David R. Meldrum — 2012-01-30

In the July 2011 issue of this Fertility and Sterility and in an online supplement we discussed various aspects of study design and the requirements for registry of clinical trials . As pointed out by Su and Sammel, when calculating the sample size required for detecting a 20% change from a high baseline, a very large number of subjects is usually required, particularly for a three-arm study. It is always better to limit such a study to only the intervention and control arms to increase its power. The study should not be terminated for lack of benefit until the planned number of randomized subjects has completed the trial; only then can a particular difference (usually 20%) be excluded with the chosen level of power (usually 80%) and significance (usually 0.05). This can require multiple centers or an extended effort in a single large center. An independent data monitoring board can be helpful because clinician-investigators naturally are impatient to find an answer. At the same time we can sympathize with the concept of a pilot study being potentially more efficient, even if not strictly correct from a biostatisticial perspective.

Outcomes of singleton births after blastocyst versus nonblastocyst transfer in assisted reproductive technology - Corrected Proof

Dhanushi Fernando, Jane L. Halliday, Susan Breheny, David Lindsay Healy — 2012-01-27

Objective: To compare obstetric and perinatal outcomes of singleton births after assisted reproductive technology (ART) with blastocyst transfer (days 5 to 6) versus nonblastocyst transfer (days 2 to 4).Design: Retrospective cohort study.Setting: Monash IVF.Patient(s): 4,202 women who conceived using in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) between 2004 and 2009.Intervention(s): Records analysis of fresh and frozen-thawed embryo transfers resulting in singleton births of at least 20 weeks’ gestation.Main Outcome Measure(s): Perinatal outcomes: preterm birth, low birthweight, very low birthweight, small for gestational age, large for gestational age, preeclampsia, antepartum hemorrhage, placental abruption, placenta previa, and postpartum hemorrhage; and covariates: maternal age, year of birth of the baby, private health insurance status, maternal body mass index, smoking status, parity, gender of baby, and variations in treatment procedures.Result(s): Multivariate analysis found no statistically significant difference between transfers on days 5 and 6 and days 2 and 4 for all maternal and perinatal outcomes. There were modest increases in the adjusted odds ratios for preeclampsia (adjusted odds ratio 1.72, 99% confidence interval 0.93–3.20) and placenta previa (1.65, 0.92–2.98).Conclusion(s): Obstetric and perinatal outcomes after blastocyst transfer on days 5 to 6 are similar when compared with embryo cleavage-stage transfers on days 2 to 4.

Transient expression of progesterone receptor and cathepsin-l in human granulosa cells during the periovulatory period - Corrected Proof

2012-01-27

Objective: To study in vivo the progesterone receptor (PR) expression levels in human granulosa cells (GCs) during the periovulatory period and the affect of the protein kinase A (PKA) pathway on PR expression and cathepsin-L expression-activation.Design: Experimental study.Setting: University research unit.Patient(s): Twenty-five women of reproductive age.Intervention(s): Follicular fluid and GCs obtained from spontaneous cycles before and during the normal luteinizing hormone surge, and samples obtained 36 hours after human chorionic gonadotropin (hCG) administration in patients undergoing in vitro fertilization.Main Outcome Measure(s): To determine PR, cathepsin-L messenger RNA (mRNA) analysis via real-time polymerase chain reaction, and protein of PR, cathepsin-L, and PKA in human GCs.Result(s): The Western blot analysis revealed that bands of PR (isoform A) were the most abundant and that mRNA (PR-A and PR-B) have a temporal pattern of expression throughout the periovulatory period. The protein levels of PR and cathepsin-L were up-regulated by hCG. The abundance of PR was diminished in the presence of PKA inhibitor, and cathepsin-L with PR receptor antagonist.Conclusion(s): The transient expression of PR in human GCs of the preovulatory follicle suggests that PR and its ligand play a role in the activation of cathepsin-L, which is presumably involved in the degradation of the follicular extracellular matrix during human ovulation.

Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment - Corrected Proof

2012-01-27

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 E2 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.

Detection of aneuploidy by array comparative genomic hybridization using cell lines to mimic a mosaic trophectoderm biopsy - Corrected Proof

Thalia Mamas, Anthony Gordon, Anthony Brown, Joyce Harper, Sioban SenGupta — 2012-01-25

Objective: To examine the effect of mosaicism in the array comparative genomic hybridization result during preimplantation genetic screening after blastocyst biopsy.Design: Experimental study.Setting: University laboratory.Material(s): Epithelial cell lines.Intervention(s): Mixing of euploid and aneuploid cells to create mosaic trophectoderm and blastocyst models.Main Outcome Measure(s): The level of aneuploidy in samples with different ratios of aneuploid cells was measured after array comparative genomic hybridization.Result(s): A shift from normality was present when the level of aneuploid cells in the sample was >25%. Aneuploidy could be confidently called when the level of aneuploid cells was >50%.Conclusion(s): This study determined that aneuploidy in mosaic samples can be detected by array comparative genomic hybridization and that the result may also indicate the proportion of the aneuploid cells present in the sample.

Sphingosine pathway deregulation in endometriotic tissues - Corrected Proof

2012-01-25

Objective: To investigate key genes expression of the sphingosine-1-phosphate pathway in endometriotic tissues.Design: A case-control laboratory study.Setting: Tertiary care university hospital.Patient(s): A total of 31 women, with (n = 16) and without (n = 15) endometriosis took part in the study.Intervention(s): After surgical excision with pathological analysis, endometrial specimens were obtained from women affected or not by endometriosis.Main Outcome Measure(s): SPHK1-2, SGPP1-2, SGPL1, SPHKAP, and S1PR1-5 messenger RNA expression by quantitative real-time polymerase chain reaction (PCR) in the endometrium of 15 disease-free women, 16 eutopic and 16 ectopic endometrium of endometriosis-affected women. The S1PR1 and S1PR2 expression were further investigated by immunohistochemistry.Result(s): The SGPP2 expression was decreased in eutopic and ectopic endometrium of endometriosis-affected women (1.7- and 16.7-fold, respectively). The SGPP1, weakly expressed in healthy endometrium, is up-regulated in endometriosis-affected women (11.9- and 64.7-fold, respectively), but its expression remains low. The SGPL1 expression was decreased in ectopic endometrium (3.3-fold) and SPHKAP expression was increased in ectopic endometrium (112.6-fold) compared with endometrium of disease-free women. In endometriosis-affected women, S1PR3 expression was decreased in eutopic and ectopic endometrium (2.1- and 6.3-fold, respectively); S1PR2 and S1PR1 expression was increased in eutopic (2.5-fold) and ectopic endometrium (2.6-fold). These increases were confirmed at the protein levels by immunohistochemistry.Conclusion(s): Expression of the enzymes implicated in the regulation of the sphingosine-1-phosphate level balance and of its receptors is overall heavily deregulated in endometriotic lesions in favor of a decreased sphingosine-1-phosphate catabolism. Our results plead for a role of the sphingosine pathway in establishing and survival of endometriotic lesions.

Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis - Corrected Proof

2012-01-24

Objective: To evaluate the role of corifollitropin alfa, a newly developed weekly administrated long-acting recombinant FSH (rFSH), as an alternative for daily rFSH administration in women undergoing controlled ovarian stimulation in GnRH antagonist down-regulated in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment cycles.Design: Systematic review and meta-analysis of randomized controlled trials.Setting: University and private centers.Patient(s): Infertile women undergoing IVF/ICSI treatment.Intervention(s): Comparing long-acting rFSH corifollitropin alfa versus standard daily administrated rFSH in GnRH antagonist IVF/ICSI cycles.Main Outcome Measure(s): Ongoing pregnancy rate, live birth rate, clinical pregnancy rate, miscarriage rate, duration of stimulation, amount of FSH, number of retrieved oocytes, number of mature oocytes, number of embryos obtained, fertilization rate, ovarian hyperstimulation syndrome (OHSS) incidence, and adverse events. Searches (of literature through November 2011) were conducted in Medline, Embase, Science Direct, the Cochrane Library, and databases of abstracts.Result(s): Four randomized trials involving 2,326 women were included. There was no evidence of a statistically significant difference in ongoing pregnancy rate for corifollitropin alfa versus rFSH. There was evidence of increased ovarian response and risk of OHSS in corifollitropin alfa.Conclusion(s): In view of its equivalence and safety profile, corifollitropin alfa in combination with daily GnRH antagonist seems to be an alternative for daily rFSH injections in normal responder patients undergoing ovarian stimulation in IVF/ICSI treatment cycles.

Severe maternal morbidity in ectopic pregnancy is not associated with maternal factors but may be associated with quality of care - Corrected Proof

2012-01-23

Objective: To study the association between patient-related risk factors and severe maternal morbidity in women with tubal ectopic pregnancy (EP). Furthermore, to identify substandard care factors in clinical care management of EP.Design: Case-control study.Setting: Not applicable.Patient(s): Case subjects were from the LEMMoN study, a prospective nationwide cohort study. Control subjects were from the ESEP study, an international multicenter randomized controlled trial.Intervention(s): Case subjects were women with tubal EP complicated by severe intra-abdominal hemorrhage necessitating blood transfusion of ≥4 units of packed red blood cells peri- or postoperatively. Control subjects were women with tubal EP who were hemodynamically stable and surgically treated.Main Outcome Measure(s): Patient-related risk factors as: maternal age, gestational age, previous EP, Chlamydia infection, pelvic inflammatory disease, assisted reproductive techniques, and serum hCG level. Substandard care categories classified as unawareness of the clinician, misdiagnosis, and nonadherence to the guideline on EP.Result(s): Twenty-nine case subjects and 99 control subjects were included. The mean serum hCG level was significantly higher in case subjects compared with control subjects, but we found no reliable cutoff level of serum hCG to rule out maternal morbidity. Other risk factors did not differ significantly. Substandard care was scored more often in case subjects (43%) than in control subjects (14%), mainly concerning misdiagnosis.Conclusion(s): No patient-related risk factors for severe intra-abdominal hemorrhage in women with tubal EP were identified. Our findings underpin the importance of awareness of EP among young fertile women and care providers and clinical care management according to the guidelines to prevent severe maternal morbidity.

Mild induced testicular and epididymal hyperthermia alters sperm chromatin integrity in men - Corrected Proof

2012-01-23

Objective: To investigate the effects of a mild induced testicular and epididymal hyperthermia (+2°C) on sperm chromatin integrity in men.Design: Experimental prospective study.Setting: University hospital.Patient(s): Five healthy fertile volunteers.Intervention(s): Testicular and epididymal hyperthermia was induced by maintaining the testes at inguinal position with the support of specially designed underwear 15 ± 1 hours daily for 120 consecutive days.Main Outcome Measure(s): Classic semen characteristics. Sperm DNA fragmentation index (DFI) and high DNA stainability (HDS) were analyzed by sperm chromatin structure assay.Result(s): Compared with baseline values, sperm DFI and HDS were significantly increased as early as day (D) 20 and D34, respectively, and remained elevated during the entire period of hyperthermia. Percentages of motile and viable spermatozoa decreased as early as D20 and D34, respectively, and total sperm count decreased at D34 during hyperthermia and remained low during the entire hyperthermia period. All studied parameters returned to respective baseline values at D73 after cessation of hyperthermia.Conclusion(s): Mild induced testicular and epididymal hyperthermia largely impaired sperm chromatin integrity, which appeared before any changes in sperm output. These findings may have clinical implications in male contraception, infertility, and assisted reproductive technology.

Fertility preservation for social indications: a cost-based decision analysis - Corrected Proof

Jennifer Hirshfeld-Cytron, William A. Grobman, Magdy P. Milad — 2012-01-23

Objective: Age-related infertility remains a problem that assisted reproductive techniques (ART) have limited ability to overcome. Correspondingly, because an increasing number of women are choosing to delay childbearing, fertility preservation strategies, initially intended for patients undergoing gonadotoxic therapies, are being applied to this group of healthy women. Studies supporting the effectiveness of this practice are lacking.Design: Decision analytic techniques.Setting: We compared the cost-effectiveness of three strategies for women planning delayed childbearing until age 40: oocyte cryopreservation at age 25, ovarian tissue cryopreservation (OTC) at age 25, and no assisted reproduction until spontaneous conception had been attempted.Patient(s): Not applicable.Intervention(s): Not applicable.Main Outcome Measure(s): Cost-effectiveness, which was defined as the cost per live birth.Result(s): In this analysis, the strategy of foregoing fertility preservation at age 25 and then choosing ART only after not spontaneously conceiving at age 40 was the most cost-effective option. OTC was dominated by the other strategies. Sensitivity analyses demonstrated the robustness of the model; no analysis existed in which OTC was not dominated by oocyte cryopreservation. Increasing the cost of an IVF cycle beyond $22,000 was the only situation in which oocyte cryopreservation was the most preferred strategy.Conclusion(s): Neither oocyte cryopreservation nor OTC appear to be cost-effective under current circumstances for otherwise healthy women planning delayed childbearing. This analysis should give pause to the current practice of offering fertility preservation based only on the desire for delayed childbearing.

Birth outcomes after spontaneous or assisted conception among infertile Australian women aged 28 to 36 years: a prospective, population-based study - Corrected Proof

Danielle L. Herbert, Jayne C. Lucke, Annette J. Dobson — 2012-01-23

Objective: To examine the extent to which the odds of birth, pregnancy, or adverse birth outcomes are higher among women aged 28 to 36 years who use fertility treatment compared with untreated women.Design: Prospective, population-based.Setting: None.Patient(s): Participants in the ALSWH born in 1973 to 1978 who reported on their infertility and use of in vitro fertilization (IVF) or ovulation induction (OI).Intervention(s): Postal survey questionnaires administered as part of ALSWH.Main Outcome Measure(s): Among women treated with IVF or OI and untreated women, the odds of birth outcomes estimated by use of adjusted logistic regression modeling.Result(s): Among 7,280 women, 18.6% (n = 1,376) reported infertility. Half (53.0%) of the treated women gave birth compared with 43.8% of untreated women. Women with prior parity were less likely to use IVF compared with nulliparous women. Women using IVF or OI, respectively, were more likely to have given birth after treatment or be pregnant compared with untreated women. Women using IVF or OI were as likely to have ectopic pregnancies, stillbirths, or premature or low birthweight babies as untreated women.Conclusion(s): More than 40% of women aged 28–36 years reporting a history of infertility can achieve births without using treatment, indicating they are subfertile rather than infertile.

Temporal trends in clomiphene citrate use: a population-based study - Corrected Proof

Sarka Lisonkova, K.S. Joseph — 2012-01-23

Objective: To examine temporal trends in clomiphene citrate use and sociodemographic characteristics associated with treatment initiation and duration.Design: Retrospective cohort study.Setting: British Columbia, Canada, 1996 to 2008.Patient(s): Women aged 20 to 49 years.Intervention(s): None.Main Outcome Measure(s): Temporal trends in treatment prevalence and incidence rates were assessed using Cochran-Armitage test for trend; differences in treatment duration were assessed using Wilcoxon and Kruskal-Wallis tests. Incidence rate ratios and 95% confidence intervals were estimated using Poisson regression.Result(s): A province-wide database of all dispensed prescriptions was used to identify clomiphene citrate users. Rural versus urban residence and neighborhood’s socioeconomic quintile were identified based on postal codes. Overall, 26,993 women were prescribed clomiphene citrate between 1996 and 2008. Prevalence rates declined from 4.1 to 3.7 clomiphene users per 1,000 women during this period, while the incidence rates remained stable (2.2 new users per 1,000 women per year). Both prevalence and incidence rates declined among women aged 20 to 29 years, and showed a statistically significant increase among women aged 30 to 44 years. Women aged 30 to 34 years had the highest incidence of clomiphene use (4.5 per 1,000 women per year). Urban residence and low versus high socioeconomic status were associated with higher rates of treatment initiation. Older age (40 to 49 years) and urban residence were associated with shorter duration of use.Conclusion(s): The increase in the incidence rates of clomiphene citrate use among women aged 30 to 44 years indicates a growing demand for fertility treatments in this population and may have contributed to the increase in multiple births.

Mayer-Rokitansky-Küster-Hauser syndrome: a review of 245 consecutive cases managed by a multidisciplinary approach with vaginal dilators - Corrected Proof

D. Keith Edmonds, Gillian L. Rose, Michelle G. Lipton, Julie Quek — 2012-01-23

Objective: To understand the efficacy of vaginal dilators in the management of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome.Design: Retrospective sequential study.Setting: Hospital.Patient(s): 245 women.Intervention(s): Vaginal dilators.Main Outcome Measure(s): Functional vaginal length and sexual satisfaction.Result(s): Of the patients who completed the program, 232 (94.9%) achieved a successful vaginal length (defined as greater than 6 cm in length and maximum width throughout the vagina and especially at the apex) and sexual function. When the program was completed by all patients, 100% of patients were successful.Conclusion(s): Vaginal dilator therapy is the treatment of first choice for creation of the vagina in MRKH syndrome, and the success rates suggest that surgery is rarely, if ever, required.

Follicle-stimulating hormone receptor gene polymorphisms are not associated with ovarian reserve markers - Corrected Proof

2012-01-23

Objective: To evaluate the association between variants in the FSHR receptor (FSHR) gene and current markers of ovarian reserve (antimüllerian hormone, antral follicle count, FSH).Design: Prospective observational study.Setting: Tertiary referral center for reproductive medicine.Patient(s): Women (n = 421) undergoing their first cycle of controlled ovarian stimulation for IVF.Intervention(s): Baseline pelvic ultrasound and blood tests were taken on day 2–3 of the cycle for assessment of baseline hormones and for DNA extraction. Genotypes for FSHR p.Asn680Ser and p.Thr307Ala variants were determined using TaqMan allelic discrimination assays.Main Outcome Measure(s): Association of FSHR single nucleotide polymorphisms with markers of ovarian reserve.Result(s): There was no evidence of any difference in basal FSH, antimüllerian hormone, or antral follicle count between the patients with different genotypes, with or without an adjustment for age or body mass index.Conclusion(s): No associations of FSHR genotypes with markers of ovarian reserve were detected in our cohort.

Adiponectin and leptin systems in human endometrium during window of implantation - Corrected Proof

2012-01-23

Objective: To measure the expression of adiponectin, leptin, and their respective receptors in the human endometria of fertile women compared with women with unexplained recurrent implantation failure (IF) during the window of implantation.Design: Controlled, prospective, clinical study.Setting: Teaching hospital and university research laboratory.Patient(s): Thirty-one endometrial biopsies from women with IF and 19 fertile controls.Intervention(s): Human endometrial biopsies.Main Outcome Measure(s): Gene and protein expression of endometrial biopsies.Result(s): Endometrial leptin expression was significantly lower in the IF group compared with fertile women. In contrast, leptin receptor (Ob-R) expression was higher in endometria of women with IF. Concerning the adiponectin system, adiponectin was expressed to the same extent in both groups. Conversely, the expression of its two receptors, AdipoR1 and AdipoR2, was reduced in endometria of women with IF compared with fertile women.Conclusion(s): Although progesterone resistance seems to be a common state of the endometrium in some human reproductive disorders, such as endometriosis or polycystic ovary syndrome, modification in leptin endometrial expression seems to be specific to IF. These results strongly suggest that changes in Ob-R and AdipoR expression profiles [1] should be implicated in the development of uterine receptivity, and [2] may therefore be potential new targets for prediction of IF.

Effect of oocyte quality on blastocyst development after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in a sheep model - Corrected Proof

2012-01-23

Objective: To compare blastocyst production, after IVF and ICSI, from sheep oocytes of various quality. Sham-injected oocytes and parthenogenetic activated oocyte groups were considered as control.Design: Prospective experimental study.Setting: University.Animal(s): Three- to 6-month-old sheep.Intervention(s): Oocyte quality was assessed with the use of brilliant cresyl blue (BCB) stain. Adenosine triphosphate content was measured. Intracytoplasmic sperm injection and IVF were performed and blastocyst development and cell numbers were analyzed.Main Outcome Measure(s): Adenosine triphosphate content, embryo development and blastomere numbers.Result(s): After IVF, BCB-stained (BCB+) oocytes developed up to the blastocyst stage at higher percentages and with more cells per embryo (24.1% vs 4.0% and 69.7 vs 43.9, respectively) than unstained (BCB−) oocytes. Using intracytoplasmic sperm injection, no differences were found in blastocyst production (14.3% vs 11.8%) and number of cells per embryo (71.1 vs 54.3) between BCB+ and BCB− oocytes. Adenosine triphosphate content was higher before in vitro maturation than after in both types of oocytes. Brilliant cresyl blue–stained oocytes had more adenosine triphosphate content than BCB− oocytes.Conclusion(s): Brilliant cresyl blue–stained oocytes show more adenosine triphosphate content than BCB− oocytes. Results from IVF were affected by the oocyte quality while ICSI did not produce differences in embryo development or blastomere numbers.

Etiology of OHSS and use of dopamine agonists - Corrected Proof

Sérgio Reis Soares — 2012-01-23

Vascular endothelial growth factor is the factor that causes increased capillary permeability and therefore the most serious manifestations of ovarian hyperstimulation syndrome. Dopamine agonists can both prevent and treat ovarian hyperstimulation syndrome by blocking expression of the vascular endothelial growth factor receptor.

Quadruplex real-time polymerase chain reaction assay for molecular diagnosis of Y-chromosomal microdeletions - Corrected Proof

Qiwei Guo, Fenghua Lan, Liangpu Xu, Yu Jiang, Li Xiao, Hailong Huang, Yulin Zhou — 2012-01-23

Objective: To develop a rapid and reliable method for molecular diagnosis of Y-chromosomal microdeletions.Design: Study of diagnostic accuracy.Setting: Molecular diagnostics laboratories in three hospitals.Patient(s): A total of 701 men with nonobstructive azoospermia or oligozoospermia from three hospitals.Intervention(s): We developed a quadruplex real-time polymerase chain reaction (PCR) assay and evaluated its performance in molecular diagnosis of Y-chromosomal microdeletions.Main Outcome Measure(s): Analytic sensitivity, analytic specificity, clinical sensitivity, and clinical specificity.Result(s): The limit of detection of quadruplex real-time PCR assay was 100 pg genomic DNA. The method attained 100% analytic specificity, 100% clinical sensitivity, and 100% clinical specificity.Conclusion(s): We have successfully upgraded the diagnostic method published by the European Academy of Andrology and the European Molecular Genetics Quality Network. Our method was validated to be fast, simple, contamination free, of high analytic sensitivity and specificity. Therefore, it is strongly suggested that such quadruplex real-time PCR assay can be readily applied as clinical routine in the near future.

Nonclassic 21-hydroxylase deficiency presenting as endometrial hyperplasia with uterine bleeding in a 67-year-old woman - Corrected Proof

Marguerite B. Vigliani, John E. Buster — 2012-01-23

Objective: To report for the first time a case of postmenopausal endometrial hyperplasia caused by nonclassic 21-hydroxylase deficiency (NC21OHD). The specific combination of mutations associated with this case has never before been reported.Design: Case report.Setting: Private academic practice.Patient(s): A 67-year-old woman with uterine bleeding due to endometrial hyperplasia was found to have premenopausal gonadotropins with elevated estrogens. Endocrine workup revealed increased 17-hydroxyprogesterone (17-OHP), which led to molecular testing to establish a diagnosis of NC21OHD.Intervention(s): Trial of suppression with low-dose oral dexamethasone.Main Outcome Measure(s): Resolution of postmenopausal bleeding.Result(s): Total estrogens normalized with treatment, and the endometrial stripe became normal.Conclusion(s): This is an unusual case of NC21OHD in which the sole presentation was persistent endometrial hyperplasia, with bleeding past the normal age for menopause. In women with unusual endometrial hyperplasias of this type, we suggest endocrine testing before proceeding to hysterectomy.

Predictors of pregnancy and live birth after insemination in couples with unexplained or male-factor infertility - Corrected Proof

2012-01-23

Objective: To identify risk factors for pregnancy outcomes in couples treated with intracervical or intrauterine insemination, with or without superovulation for unexplained or male-factor infertility.Design: Secondary analysis of data from a randomized superovulation and intrauterine insemination trial.Setting: Academic medical centers.Intervention(s): Treatment continued for four cycles unless pregnancy was achieved.Patient(s): Out of 932 couples randomized to four treatment groups, 664 couples who had completed the lifestyle questionnaires were assessed for occurrence of pregnancy and live birth.Main Outcome Measure(s): Pregnancy and live birth.Result(s): The pregnancy and live birth rates were significantly higher in couples in which the female partners reported that they had consumed coffee or tea in the past or drank alcoholic beverages in the past (past users) compared with those who had never consumed coffee, tea, or alcoholic beverages. Past users also had significantly higher pregnancy and live birth rates than those currently consuming coffee or tea or alcoholic beverages. Demographic, occupational exposure, and other lifestyle factors were not significant.Conclusion(s): Couples in which the female partners drank coffee, tea, or alcoholic beverages in the past had higher pregnancy and live birth rates compared with never or current users. When discontinuing these habits, they might have made other lifestyle changes to improve the pregnancy outcome.

Can the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) be used to accurately report clinic total reproductive potential (TRP)? - Corrected Proof

2012-01-23

Objective: To assess whether total reproductive potential (TRP), the chance of a live birth from each fresh cycle (fresh cycle plus frozen transfers), could be calculated from the national Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database and whether information not available in SART CORS resulted in significant changes to the TRP calculation.Design: Retrospective study using SART CORS and clinic data.Setting: Three assisted reproductive technology clinics.Patient(s): Women undergoing ART.Intervention(s): None.Main Outcome Measure(s): Two- and three-year TRPs for 2005 and 2006 were calculated according to patient age at cycle start by linking fresh to frozen cycles up to first live birth. Clinic records were used to adjust for (remove) frozen cycles that used more than one fresh cycle as a source of embryos and for any embryos donated to other patients or research or shipped to another facility before a live birth.Result(s): TRP was higher than fresh per-cycle rates for most ages at all clinics, although accuracy was compromised when there were fewer than 20 cycles per category. Two- and 3-year TRPs differed in only 2 of 24 calculations. Adjusted TRPs differed less than three percentage points from unadjusted TRPs when volume was sufficient.Conclusion(s): Clinic TRP can be calculated from SART CORS. Data suggest that calculations of clinic TRP from the national dataset would be meaningful.

Preventing severe OHSS has many different facets - Corrected Proof

David R. Meldrum — 2012-01-23

Only 20 years ago we had no understanding of what causes OHSS. The review by Soares chronicles a remarkable story defining granulosa cell (GC) VEGF as the mediator of this syndrome, culminating in treatment with dopamine agonists that block VEGF receptor expression as the cause of increased vascular permeability. I was fortunate to be part of an elegant study by Levin and colleagues using a bioassay for vascular permeability showing that 98% of the bioactivity of follicular fluid in high responders was blocked by an anti-VEGF antibody. Other purported mediators of the syndrome must therefore play a very limited role.

Pre-emptive effect of ibuprofen versus placebo on pain relief and success rates of medical abortion: a double-blind, randomized, controlled study - Corrected Proof

2012-01-20

Objective: To determine the efficacy of pre-emptive administration of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen vs. a placebo on pain relief during medical abortion and to evaluate whether NSAIDs interfere with the action of misoprostol.Design: Prospective, double-blind, randomized, controlled study.Setting: University-affiliated tertiary hospital.Patient(s): Sixty-one women who underwent first-trimester termination of pregnancy.Intervention(s): Patients received 600 mg mifepristone orally, followed by 400 μg oral misoprostol 2 days later. They were randomized to receive pre-emptively two tablets of 400 mg ibuprofen orally or a placebo, when taking the misoprostol. The patients completed a questionnaire about side effects and pain score and returned for an ultrasound follow-up examination 10–14 days after the medical abortion.Main Outcome Measure(s): Significant pain, assessed by the need for additional analgesia, and failure rates, defined by a need for surgical intervention.Result(s): Pre-emptive ibuprofen treatment was found to be more effective than a placebo in pain prevention, as determined by a significantly lower need for additional analgesia: 11 of 29 (38%) vs. 25 of 32 (78%), respectively. Treatment failure rate was not statistically different between the ibuprofen and placebo groups: 4 of 28 (14.2%) vs. 3 of 31 (9.7%), respectively. History of menstrual pain was predictive for the need of additional analgesia.Conclusion(s): Pre-emptive use of ibuprofen had a statistically significant beneficial effect on the need for pain relief during a mifepristone and misoprostol regimen for medical abortion. Ibuprofen did not adversely affect the outcome of medical abortion.Clinical Trial Registration Number: NCT00997074.

Epistasis between the HSD17B4 and TG polymorphisms is associated with premature ovarian failure - Corrected Proof

Jung-A Pyun, Sunshin Kim, Dong Hyun Cha, Jeong-Jae Ko, KyuBum Kwack — 2012-01-20

Objective: To identify whether epistasis between TG and HSD17B4 and whether polymorphisms in HSD17B4 are associated with premature ovarian failure (POF).Design: Case-control genetic association study.Setting: Research laboratory of a university.Patient(s): Female patients with POF (98) and controls (218) of Korean ethnicity participated in this study.Intervention(s): None.Main Outcome Measure(s): Genotype distribution, haplotype (HT) inference, and gene–gene interaction.Result(s): Distribution of one haplotype (A-G-A-A-G-G) on the HSD17B4 gene was significantly different between the POF group and the control group in a dominant model. In addition, the combined effect of the single nucleotide polymorphisms (SNPs) HSD17B4 rs28943592 and TG rs2076740 was significantly associated with POF (odds ratio = 7.74, 95% confidence interval = 1.67–35.94), although a significant association was not observed in the single SNP model.Conclusion(s): A haplotype in the HSD17B4 gene was identified that was significantly associated with resistance to POF. In addition, epistasis between two missense SNPs (rs28943592, rs2076740) located in HSD17B4 and TG was significantly associated with susceptibility to POF.

Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway - Corrected Proof

2012-01-20

Objective: To clarify the role and mechanism of CCL2 in regulating the biological functions of endometrial stromal cells (ESCs).Design: The CCL2 effect on the viability, proliferation, and invasion in the eutopic ESCs from endometriosis.Setting: Research laboratories.Patient(s): Patients with endometriosis aged 23–47 years.Intervention(s): None.Main Outcome Measure(s): Signal transduction and downstream molecules from CCR2.Result(s): We have found that the secretion of CCL2 by the eutopic ESCs from endometriosis is higher than that of healthy ESCs without endometriosis. The CCL2 can enhance the viability, proliferation, and invasion of ESCs in a dosage and time-dependent manner. Anti-CCL2 neutralizing antibody and CCR2 antagonist can completely abolish the increase in viability, proliferation, and invasiveness of ESCs induced by CCL2. The CCL2 can increase the expression of proliferating cell nuclear antigen, survivin, and matrix metalloproteinase 2, and decrease the expression of tissue inhibitor of metalloproteinase 1 and 2, and promote the viability, proliferation and invasiveness of ESCs by activating Akt and MAPK/Erk1/2 signal pathway, but not p38 and JNK signal pathway.Conclusion(s): CCL2 might play an important role in regulating the functions of ESCs through Akt and MAPK/Erk1/2 signal pathway, and overexpression of CCL2 in ESCs and peritoneal fluid (PF) would lead to onset and development of endometriosis.

Is cryopreservation of embryos a legitimate surrogate marker of embryo quality in studies of assisted reproductive technology conducted using national databases? - Corrected Proof

Judy E. Stern, Ellice S. Lieberman, Maurizio Macaluso, Catherine Racowsky — 2012-01-20

Objective: To investigate whether cryopreservation of supernumerary embryos is a good surrogate for embryo quality.Design: Retrospective study of 6,859 assisted reproductive technology (ART) cycles from women aged <35 years with two fresh day 3 embryos transferred.Setting: National Society for Assisted Reproductive Technology Clinic Outcome Reporting System data from 2006–2008.Patient(s): Women undergoing ART.Intervention(s): None.Main Outcome Measure(s): Embryo quality (good, fair, or poor), cell number, and live births were compared for cycles with and without cryopreservation, using χ2 to evaluate statistical significance. The association of freezing with embryo quality was examined using multiple logistic regression after adjusting for confounders (patient age, oocyte yield, intracytoplasmic sperm injection [ICSI], assisted hatching, male factor infertility).Result(s): Cycles with cryopreservation were more likely to have two embryos of good quality transferred (81.3% vs. 48.5%) and had more 8-cell embryos transferred (76.0% vs. 50.1%). Relative to cycles with two good embryos (good-good), the adjusted odds ratios (OR) for cryopreservation were: good-fair (OR = 0.301, 95% confidence interval [CI] = 0.257–0.354), fair-fair (OR = 0.308, 95% CI = 0.258–0.367), and any poor (OR = 0.058, 95% CI = 0.040–0.083). The live birth rate was 52.4% for cycles with freezing and 40.6% for cycles without.Conclusion(s): Embryo quality and cell number were both associated with embryo cryopreservation. However, although cryopreservation was a strong marker for good quality, not having cryopreservation did not reliably indicate poor quality, as almost half of those cycles had two good quality embryos.

Agonist and antagonist coast - Corrected Proof

Mohamed Aboulghar — 2012-01-20

The use of GnRH-a in ovarian stimulation permitted stronger stimulation resulting in an increased incidence of OHSS. The first Cochrane review comparing GnRH agonist and GnRH antagonist protocols for ovarian stimulation showed no significant difference in OHSS rate between the two protocols, however, a recent Cochrane review showed a highly significant decrease in the incidence in OHSS rate in the antagonist protocol. Coasting is a commonly used procedure for preventions of OHSS. The optimum time to start coasting is when the lead follicle reaches 16 mm in diameter and hCG should be given when E2 level drops below 3000 pg/ml. Coasting may act by diminishing the functioning granulosa cell cohort. Administration of daily GnRH antagonist in high risk patients for OHSS who were down-regulated by GnRH-a resulted in rapid drop of E2 and decrease in incidence of OHSS. A series of patients who developed early OHSS were treated by daily GnRH antagonist injections, all embryos were cryopreserved. No progression to severe OHSS was observed.

Risk of obstructive sleep apnea in obese and nonobese women with polycystic ovary syndrome and healthy reproductively normal women - Corrected Proof

Babak Mokhlesi, Bert Scoccia, Theodore Mazzone, Susan Sam — 2012-01-19

Objective: To study the risk for obstructive sleep apnea (OSA) in a group of nonobese and obese polycystic ovary syndrome (PCOS) and control women.Design: Prospective study.Setting: Academic tertiary care medical center.Patient(s): Forty-four women with PCOS and 34 control women.Intervention(s): All of the women completed the Berlin questionnaire for assessment of OSA risk.Main Outcome Measure(s): All of the women underwent fasting determination of androgens, glucose, and insulin.Result(s): Women with PCOS were more obese compared with control women. However, there were no differences in BMI once subjects were divided into nonobese (PCOS: n = 17; control: n = 26) and obese (PCOS: n = 27; control: n = 8) groups. Women with PCOS had higher prevalence of high-risk OSA compared with control women (47% vs. 15%). However, none of the nonobese PCOS and control women screened positively for high-risk OSA. Among the obese group, the risk did not differ between groups (77% vs. 63%).Conclusion(s): Our findings indicate that even though the risk for OSA in PCOS is high, it is related to the high prevalence of severe obesity. The risk for OSA among nonobese women with PCOS is very low. However, our findings are limited by lack of polysomnographic confirmation of OSA.

Oocyte mitochondrial bioenergy potential and oxidative stress: within-/between-subject, in vivo versus in vitro maturation, and age-related variations in a sheep model - Corrected Proof

2012-01-18

Objective: To analyze within-/between-subject, in vivo versus in vitro maturation (IVM), and age-related variations of mitochondrial (mt) bioenergy potential and oxidative status of metaphase II (MII) oocytes recovered from hormonally stimulated sheep.Design: Prospective study.Setting: Academic basic research laboratory.Subject(s): Ten adult ewes.Intervention(s): Estrus synchronization, controlled ovarian hyperstimulation (COH), ovariohysterectomy; follicular and oviductal oocyte retrieval; IVM of follicular oocytes.Main Outcome Measure(s): Mean ± SD, within-subject (CVw) and between-subject (CVb) variation coefficients of mt activity, intracellular reactive oxygen species (ROS) levels, and mt/ROS colocalization in sheep oocytes from young and aged donors and matured in vivo (in vivo MIIs) or in vitro (IVM MIIs).Result(s): Within- and between-subject, in vivo versus IVM, and age-related variations of mt activity were observed in MII oocytes from hormonally stimulated donor sheep. ROS levels increased significantly in oocytes from aged donors. Mt-ROS colocalization was consistently higher in in vivo MIIs compared with IVM MIIs. Oviductal energy/antioxidant ability is influenced by COH.Conclusion(s): Oocyte energy/oxidative status is affected by within-/between-subject, in vivo versus IVM, and age-related variations. Mt/ROS colocalization is a reliable marker of in vivo MII oocytes.

Does colorectal endometriosis alter intestinal functions? A prospective manometric and questionnaire-based study - Corrected Proof

2012-01-18

Objective: To objectively evaluate using anorectal manometry whether endometriotic nodules influence intestinal function and to reveal subjective intestinal dysfunctions in patients with rectosigmoid deep infiltrating endometriosis.Design: Prospective study.Setting: Tertiary care university hospital.Patient(s): Patients (n = 25) with a preoperative diagnosis of rectosigmoid endometriosis.Intervention(s): Patients underwent anorectal manometry; after that, they filled a questionnaire about defecatory functions and ranked their pain symptoms.Main Outcome Measure(s): The parameters studied were resting pressure, maximum squeezing pressure, pushing, rectoanal inhibitory reflex, and rectal sensibility. We analyzed the responses to the defecatory function questionnaire and the scored the endometriosis pain symptoms using a Visual Analogue Scale.Result(s): No alterations of the rectoanal inhibitory reflex were found. Hypertone of the internal anal sphincter was found in 20 of 25 patients. Almost half of the patients had an increase of the threshold of desire to defecate, and 7 patients had a reduction of the anal sphincter squeeze pressure. According to the responses to the defecatory function questionnaire, incomplete evacuation was the most common symptom.Conclusion(s): We did not find marked motility or sensitive dysfunctions at the anorectal manometry, whereas subjectively patients reported some defecatory disorders. We revealed the presence of hypertone of the internal anal sphincter in most of the patients.Clinical Trial Registration Number: 74/2010/O/Sper.

Thyroid function during controlled ovarian hyperstimulation as part of in vitro fertilization - Corrected Proof

2012-01-18

Objective: To determine the exact nature and timing of alterations in thyroid function throughout controlled ovarian hyperstimulation (COH).Design: Prospective cohort study.Setting: University fertility clinic.Patient(s): Fifty-seven women undergoing COH as part of planned in vitro fertilization.Intervention(s): None.Main Outcome Measure(s): Timing and magnitude of change in serum thyroid hormones, including TSH, total and free T4, E2, and thyroxine-binding globulin (TBG), measured at six time points from before stimulation to 2 weeks after serum pregnancy test.Result(s): Geometric mean serum TSH increased during stimulation, peaking 1 week after hCG administration compared with baseline (2.44 vs. 1.42 mIU/L), as did free T4 (1.52 vs. 1.38 ng/dL) and TBG (32.86 vs. 21.52 μg/mL). Estradiol levels increased, peaking at hCG administration (1743.21 vs. 71.37 pg/mL). Of 50 women with baseline TSH ≤2.5 mIU/L, 22 (44.0%) had a subsequent rise in TSH to >2.5 during or after COH. The pattern of change over time in TSH concentrations was significantly influenced by baseline hypothyroidism and whether pregnancy was achieved.Conclusion(s): COH led to significant elevations in TSH, often above pregnancy appropriate targets. These findings were particularly evident in women with preexisting hypothyroidism and may have important clinical implications for screening and thyroid hormone supplementation.

High expression of luteinizing hormone receptors messenger RNA by human cumulus granulosa cells is in correlation with decreased fertilization - Corrected Proof

2012-01-18

Objective: To elucidate the LH receptor (LHR) expression patterns in human granulosa cells (GCs) from antral to preovulatory stages, and to investigate a correlation to oocyte function.Design: Luteinized preovulatory GCs were obtained from preovulatory follicles aspirated during IVF (≥17 mm). The GCs from small- (<10 mm) and medium-sized (10–15 mm) follicles were obtained during in vitro maturation (IVM) procedures. Cumulus GCs were obtained during oocyte denudation for intracytoplasmatic sperm injection (ICSI) procedures (IVF).Setting: Referral center.Patient(s): Seventy IVF patients and 20 IVM patients.Intervention(s): GC collection.Main Outcome Measure(s): The LHR expression levels in mural and cumulus GCs of different follicular sizes and their correlation to oocyte outcome.Result(s): The LHR expression increased with follicle size and was higher in mural GCs compared with cumulus cells. The LHR expression in cumulus GCs from preovulatory follicles was higher in metaphase II (MII) oocytes than in metaphase I or germinal vesicle oocytes (IVF). Unexpectedly, higher expression of LHR in cumulus GCs of MII oocytes correlated with decreased fertilization rates.Conclusion(s): The LHR expression in small follicles obtained in IVM suggests a role for hCG administration during IVM procedures. Overexpression of LHR in cumulus GCs of MII oocytes may signal malfunction of oocytes and low fertilization capacity.

Comment on, “Increase of success rate for women undergoing embryo transfer by transcutaneous electrical acupoint stimulation: a prospective randomized placebo-controlled study” - Corrected Proof

Sergio P. Gonçalves — 2012-01-18

It is widely known that embryo quality affects pregnancy and live birth rates. Nevertheless, in their article, “Increase of success rate for women undergoing embryo transfer by transcutaneous electrical acupoint stimulation: a prospective randomized placebo-controlled study,” Zhang et al. do not mention the quality of transferred embryos at all. In addition, there is no information about ovarian stimulation protocols (GnRH agonist? GnRH antagonist? recombinant or urinary FSH?), length of stimulation, endometrial thickness or day of embryo transfer. One might expect day-5 cycles to be different, for better or worse, considering that the interval between intervention (transcutaneous electrical acupoint stimulation [TEAS]) and embryo implantation would have been shorter.

Reply of the authors - Corrected Proof

Rong Zhang, Ji-Sheng Han — 2012-01-18

We welcome Dr Gonçalves’ comment on our study and present our answers. Concerning embryo quality, only high quality embryos were chosen for transfer. No significant differences were found in the number of high quality embryos among the three groups (mock TEAS: 4.8 ± 4.1, single TEAS: 5.5 ± 3.3, and double TEAS: 5.2 ± 4.4).

Sexuality after sigmoid vaginoplasty in patients with Mayer-Rokitansky-Küster-Hauser syndrome - Corrected Proof

Caroline Carrard, Marie Chevret-Measson, Aude Lunel, Daniel Raudrant — 2012-01-16

Objective: To investigate the functional and sexual outcome of sigmoid vaginoplasty in patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome.Design: Prospective study.Setting: University hospital.Patient(s): Fifty-nine consecutive patients with MRKH syndrome.Intervention(s): Forty-eight patients underwent sigmoid vaginoplasty, and 11 were treated using the Frank method of dilatation.Main Outcome Measure(s): Functional results and sexuality were evaluated with the use of two standardized questionnaires: the Female Sexual Function Index (FSFI) and the revised Female Sexual Distress Scale (FSDS-R). Questions were added to analyze depression, body image perception, and desire of motherhood.Result(s): Out of the 68% of patients who answered the questionnaire, 73% had regular sexual intercourse. The mean total FSFI score was 28 ± 3.1 in the operated group and 30 ± 5.3 in the group treated with the Frank method. Their mean FSDS-R scores were 21 ± 12.1 and 18 ± 13.8, respectively.Conclusion(s): Sigmoid vaginoplasty is an effective technique providing a nearly normal sexual function to patients with vaginal aplasia. Despite this, psychologic distress related to sexuality persists in most patients, demonstrating the need for a multidisciplinary support.

Agonist trigger with aggressive luteal support - Corrected Proof

Lawrence Engmann, Claudio Benadiva — 2012-01-16

Although gonadotropin-releasing hormone agonist (GnRHa) trigger is effective in the prevention of ovarian hyperstimulation syndrome, lower conception rates have been reported. Intensive luteal phase support is an effective approach to improve implantation rates in women with peak E2 levels ≥4,000 pg/mL. However, patients with peak E2 levels <4,000 pg/mL may require a dual trigger with GnRHa and 1,000 IU hCG and intensive luteal phase support to improve implantation rates.

The relationship between follicle development and progesterone receptor membrane component-1 expression in women undergoing in vitro fertilization - Corrected Proof

Alyaa Elassar, Xiufang Liu, Victoria Scranton, Carol A. Wu, John J. Peluso — 2012-01-16

Objective: To determine the relationship between progesterone receptor membrane component-1 (PGRMC1) expression and the outcome of IVF treatment.Design: A prospective study in which PGRMC1 messenger RNA (mRNA) levels, methylation status of the Pgrmc1 promoter, and the presence of point mutations within Pgrmc1 were obtained from granulosa (GC)/luteal cells of women undergoing controlled ovarian hyperstimulation (COH).Setting: Fertility center/basic science laboratory.Patient(s): Eighty-five patients undergoing IVF treatment and 10 women who were undergoing COH for the purpose of oocyte donation were included in this study.Intervention(s): None.Main Outcome Measure(s): The PGRMC1 measurements were correlated with clinical outcomes, such as number of follicles, number of retrieved oocytes, and ongoing pregnancy rates (PR).Result(s): The PGRMC1 mRNA levels within GC/luteal cells of 18% of IVF patients were >2.25-fold higher than those of oocyte donors. Individuals with elevated PGRMC1 mRNA levels had 30% fewer large follicles and fewer oocytes retrieved. The elevated PGRMC1 mRNA levels were associated with an increase in the methylation of Pgrmc1 promoter.Conclusion(s): In patients with elevated PGRMC1 mRNA levels, gonadotropin-induced follicle development is attenuated, although sufficient numbers of follicles develop to allow for ET and subsequent pregnancy.

Developmental programming: prenatal testosterone excess disrupts anti-Müllerian hormone expression in preantral and antral follicles - Corrected Proof

Almudena Veiga-Lopez, Wen Ye, Vasantha Padmanabhan — 2012-01-16

Objective: To investigate the impact of prenatal T excess on the expression of key ovarian regulators implicated in follicular recruitment and persistence using a large animal model of polycystic ovarian syndrome (PCOS).Design: Interventional, animal model study.Setting: Academic research unit.Animal(s): A total of 25 female fetuses, 14 prepubertal female, and 24 adult female Suffolk sheep.Intervention(s): Prenatal T treatment.Main Outcome Measure(s): Immunohistochemical determination of expression of anti-Müllerian hormone (AMH), kit ligand, and growth differentiation factor 9 (GDF9) in fetal, prepubertal, and adult ovarian tissues.Result(s): Prenatal T treatment reduced the AMH protein expression in granulosa cells (GC) of preantral follicles and increased its expression in antral follicles compared with age-matched adult controls. These differences were not evident in prepubertal animals. Protein expression of GDF9 and kit ligand was not altered at any of the developmental time points studied.Conclusion(s): Prenatal T exposure is associated with changes in AMH expression in preantral and antral follicles in adult ovaries, similar to findings in women with PCOS. These findings indicate that abnormal folliculogenesis in PCOS may be at least in part mediated by changes in AMH expression.