Fertility and Sterility

Testing the water before swimming: satisfying the need for clinical trials of devices, media, and instruments before their use in assisted reproduction laboratories

Nicolás Garrido, Antonio Pellicer, Craig Niederberger — 2011-12-14

The steady progress of assisted reproduction technologies (ART) realized significant improvements that increase the chance of delivering healthy offspring to parents suffering with infertility. Developments in ART laboratories, such as the introduction of new devices, instruments, and the evolution of culture media formulations, were crucial to this success. At present, laboratories and ART-related technology are light years from those that existed when the first test-tube babies were born.

Contemporary aspects of male gamete (dys)function: aiming towards optimizing the treatment of fertilization disorders

Zev Rosenwaks, Gianpiero D. Palermo — 2012-02-01

At its inception, in vitro fertilization (IVF) was a relatively straightforward procedure encompassing the in vitro insemination of surgically retrieved oocytes and the trans-cervical uterine placement of the ensuing embryos with the goal of overcoming tubal infertility. Since that time, IVF has become the ultimate treatment modality for all infertility indications when standard treatments have failed. While IVF has revolutionized our clinical armamentarium, it has also served as a remarkable scientific tool allowing direct visualization of male and female gamete interaction and assessment of human embryo development, thus enabling reproductive specialists to dissect and better understand the early human reproductive processes. In its earliest stages, IVF was directed at the treatment of female infertility focusing on the role of the oocyte, later to be eclipsed by assisted fertilization techniques that revolutionized the treatment of male factor infertility. The advent of assisted fertilization techniques, from the most simplistic approaches to direct sperm injection, has made it possible for suboptimal male gametes to penetrate the oocyte vestments. The latter technique has shed light on the ultimate function of the spermatozoon and the fascinating process of syngamy. Moreover, the ability to temporally monitor the cleaving embryo in vitro has enabled us to ascertain the individual steps involved in the development of the conceptus from syngamy to blastocyst as well as to shed light on hitherto unapproachable infertility etiologies.

Development and current applications of assisted fertilization

2012-02-01

Since the very early establishment of in vitro insemination, it became clear that one of the limiting steps is the achievement of fertilization. Among the different assisted fertilization methods, intracytoplasmic sperm injection emerged as the ultimate technique to allow fertilization with ejaculated, epididymal, and testicular spermatozoa. This work describes the early steps that brought forth the development of intracytoplasmic sperm injection and its role in assisted reproductive techniques. The current methods to select the preferential male gamete will be elucidated and the concerns related to the offspring of severe male factor couples will be discussed.

Semen analysis: looking for an upgrade in class

Christopher De Jonge — 2012-02-01

Objective: To review the literature database regarding current methods for diagnosing male subfertility and to critique new testing methods that have the potential to be incorporated as part of routine semen analysis.Design: Literature database review.Setting: None.Patient(s): None.Intervention(s): None.Main Outcome Measure(s): None.Result(s): Methods for performing high quality semen analysis are standardized and clearly presented in the 2010 World Health Organization (WHO) laboratory manual for the examination and processing of human semen. In spite of the fact that lower reference limits contained therein are now evidence-based, debate persists about their clinical value. One test put forth as being additive to the semen analysis is assessment of DNA integrity. However, due to lack of standardized methods and quality control measures, accessibility to instrumentation, and evidence-based reference values for clinical interpretation this test has not become incorporated into the clinical andrology mainstream. Novel tests that probe molecular function have emerged that also have promise for integration into routine clinical semen analysis.Conclusion(s): Semen analysis, when performed according to WHO guidelines, will yield accurate and precise clinical laboratory data on traditional semen parameters. Due to the biological nature of the specimen in question definitive diagnosis of subfertility and its cause(s) remains enigmatic. Novel tests that may be easily standardized for subsequent multi-center, prospective randomized trials need to be integrated so more meaningful clinical diagnoses can be made.

Epigenetics of the male gamete

Douglas T. Carrell — 2012-02-01

Objective: To review and summarize the current understanding of the epigenetic status of human sperm in regards to protamination, specific localization and modifications of retained histones, and DNA methylation.Design: Review of the relevant literature.Setting: University-based clinical and research laboratories.Patient(s): Fertile and infertile men.Intervention(s): None.Main Outcome Measure(s): Critical review of the literature.Result(s): Sperm from normospermic, fertile men have epigenetic modifications consistent with gene “poising” at the promoters of genes involved in development, including the localization of retained histones with bivalent histone modifications and hypomethylation of DNA. These epigenetic marks are altered in some patients with abnormal spermatogenesis, and in some men who exhibit unexplained, altered embryogenesis during IVF therapy.Conclusion(s): The sperm epigenome implies a poising of the paternal genome for embryogenesis and a possible role in the establishment of totipotency of the embryo and may help in understanding some causes of reduced fertility and transmission of disease risk.

Human spermatozoal RNAs

Toshio Hamatani — 2012-02-01

Objective: To provide a focused review of the scientific literature pertaining to spermatozoal RNA.Design: Review of the literature and appraisal of relevant articles.Setting: Not applicable.Patient(s): Infertile male.Intervention(s): None.Main Outcome Measure(s): Spermatozoal RNAs as potential epigenetic modifiers in early embryo development and as clinical markers of male infertility.Result(s): The nucleus of mature spermatozoa contains a complex population of mRNAs and miRNAs despite its transcriptionally inert state.Conclusion(s): A specific set of functional RNAs are delivered into oocytes during fertilization and are thought to contribute extragenomically to early embryonic development. Even if spermatozoal RNAs is merely residual, it still has the potential to greatly improve the investigative and diagnostic potential of male infertility.

Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome

Practice Committee of the American Society for Reproductive Medicine — 2011-12-22

In women with Turner syndrome, the risk of death from aortic dissection or rupture during pregnancy may be 2%, and this risk persists during the postpartum period owing to pregnancy-related aortic changes. Turner syndrome is a relative contraindication for pregnancy; however, it is an absolute contraindication for pregnancy in a patient with a documented cardiac anomaly. This document replaces the 2008 document of the same name.

Genome-wide sperm deoxyribonucleic acid methylation is altered in some men with abnormal chromatin packaging or poor in vitro fertilization embryogenesis

Kenneth I. Aston, Vasu Punj, Lihua Liu, Douglas T. Carrell — 2011-12-09

Objective: To evaluate genome-wide DNA methylation patterns in sperm from men with abnormal sperm chromatin packaging and patients displaying abnormal embryogenesis after IVF in the absence of known female factors.Design: Case–control study.Setting: University andrology and research laboratory.Patient(s): Men with abnormally high and low protamine 1/protamine 2 ratio (n = 15); patients who have undergone IVF/intracytoplasmic sperm injection resulting in abnormal embryogenesis (n = 13); and normozoospermic, fertile controls (n = 15).Intervention(s): Genome-wide sperm DNA methylation was measured using the Illumina Infinium HumanMethylation27 BeadChip assay. Follow-up targeted methylation analysis was performed using bisulfite pyrosequencing.Main Outcome Measure(s): Methylation levels at more than 27,000 CpGs genome-wide were compared between groups.Result(s): Of the 43 men analyzed, 40 displayed highly concordant methylation patterns; however, two men with abnormal protamine 1/protamine 2 and one abnormal embryogenesis patient displayed significantly altered methylation patterns across a large number of CpGs. Imprinted regions were more prone to deregulation than the genome at large.Conclusion(s): We have identified three individuals displaying broad disruption of sperm DNA methylation profiles. Although the sample set analyzed is relatively small, these results indicate that broad disruptions in sperm DNA methylation may be an important signature in some infertile men. Functional studies will be necessary to characterize the developmental consequences of such epigenetic disruption.

Superoxide dismutase content in sperm correlates with motility recovery after thawing of cryopreserved human spermatozoa

2011-12-09

Objective: To investigate the correlation between sperm superoxide dismutase (SOD) content and motility recovery after thawing of cryopreserved human sperm, based on the rationale that this antioxidant enzyme provides protection against reactive oxygen species-induced damage during cryopreservation.Design: Prospective study.Setting: Private infertility institute and university-based research laboratory.Patient(s): Forty-two consenting normozoospermic patients consulting for infertility.Intervention(s): The SOD content was measured in sperm from unfractionated samples and in sperm recovered from the pellet fraction obtained after discontinuous density gradient centrifugation.Main Outcome Measure(s): Sperm motility was evaluated post-thaw in the two sets of samples and motility recovery was plotted against the sperm SOD content to determine their correlation.Result(s): There was a significant positive correlation between motility recovery after thawing and SOD content in sperm from the 90% gradient pellet containing highly purified mature sperm. There was also a significant negative correlation between motility after thawing and SOD content in the unfractionated sample.Conclusion(s): The positive correlation between post-thaw motility recovery and SOD content in mature spermatozoa provides a good predictor of post-thaw motility recovery after cryopreservation.

The utility and cost of Chlamydia trachomatis and Neisseria gonorrhoeae screening of a male infertility population

2011-12-22

Objective: To determine the utility and cost of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) screening in infertile males.Design: Cohort study.Setting: Canadian tertiary-level male infertility clinic and university-affiliated laboratories.Patient(s): 5,588 male infertility patients.Intervention(s): CT and NG testing on 8,972 urine and semen samples.Main Outcome Measure(s): Prevalence of CT and NG infection in infertile males versus general male population in Canada over 8 years (2003–2010) and the reagent cost to detect one case of CT or NG.Result(s): In infertile males, the prevalence rate for CT and NG was 0.304% and 0.0537%, which was statistically significantly lower (3.4- and 8.1-fold lower, respectively) than the age-adjusted general population prevalence. With the reagents costing $86.20 per patient tested, the reagent cost alone to diagnose one case of CT or NG was $38,669.Conclusion(s): The prevalence of CT and NG in this study are among the lowest reported in the male infertility literature. These findings question the utility of CT/NG screening in this low-risk population and emphasize that decisions about the utility of screening must be based on the prevalence rates of the disease in the studied population.

The management of retrograde ejaculation: a systematic review and update

Amanda Jefferys, Dimitrios Siassakos, Peter Wardle — 2011-12-15

Objective: To determine the best management of retrograde ejaculation to optimize the chance of conception.Design: Systematic review.Setting: Tertiary reproductive medicine center.Patient(s): Subfertile men with retrograde ejaculation.Method(s): Systematic search of studies using search terms “management” or “therapy” or “treatment” and “retrograde ejaculation.” We excluded case reports and papers not in English.Main Outcome Measure(s): Pregnancy and live birth rates and rates of achievement of antegrade ejaculation.Result(s): Thirty-four studies met our criteria. Studies were mostly observational. Descriptions of predictive and confounding variables were often insufficient. The treatment options included urinary sperm retrieval and medical management with anticholinergics and sympathomimetics. Successful pregnancies and live births were also achieved using surgical techniques and electroejaculation; however, numbers were small.Conclusion(s): Many treatment options exist in the management of retrograde ejaculation; however, current literature is insufficient to allow firm comparisons between interventions. Treatment should be tailored, therefore, to the individual. Our findings support the need for further research in this area—including large randomized controlled trials. However, these would be difficult logistically and may not be possible.

Normal live birth after testicular sperm extraction and intracytoplasmic sperm injection in variant primary ciliary dyskinesia with completely immotile sperm and structurally abnormal sperm tails

2011-12-02

Objective: To report on the investigation and fertility management of variant primary ciliary dyskinesia (PCD).Design: Case report.Setting: University-affiliated assisted reproductive technologies practice.Patient(s): A 40 year-old man presenting with 12 months’ primary infertility, complete sperm immotility, severe morphologic defects, and moderate sinopulmonary disease.Intervention(s): Electron microscopy (EM) of sperm, nasal cilial function studies, open testis biopsy, and sperm extraction for intracytoplasmic sperm injection (ICSI).Main Outcome Measure(s): Outcome of ICSI treatment using immotile testicular sperm.Result(s): EM revealed abnormal connecting pieces, shortened midpieces with attenuated mitochondrial sheaths, poorly developed annulus, abnormal outer dense fibers, and axonemes missing the two central mircotubules. Nasal ciliary beat frequency was subnormal and dyssynchronous. Immotile testicular sperm were selected for ICSI based on physical characteristics and fertilized 12 of 18 eggs. A single day-5 blastocyst achieved a normal pregnancy and delivery of a healthy 3,840-g girl at 38 weeks’ gestation.Conclusion(s): Nonclassic PCD may present with structurally abnormal completely immotile sperm, with seemingly little prospect of fertility, and moderate respiratory dysfunction supporting the presence of an underlying ciliopathy. Despite testicular sperm also being immotile and showing profound structural defects that would seem to preclude fertilization, more morphologically normal sperm are capable of establishing a normal pregnancy.

Presence of spermatogonia in 47,XXY men with no spermatozoa recovered after testicular sperm extraction

Dorien Van Saen, Herman Tournaye, Ellen Goossens — 2011-12-02

Objective: To evaluate the presence of spermatogonia in men diagnosed with Klinefelter syndrome (KS), in whom no testicular spermatozoa were recovered by testicular sperm extraction.Design: Retrospective case series.Setting: University hospital.Patient(s): Testicular samples from 22 nonmosaic 47,XXY men, aged 24–43 years, with no spermatozoa at multiple biopsies.Intervention(s): Paraffin-embedded testicular tissue was sectioned and stained with hematoxylin-eosin, and immunostainings were performed for both MAGE-A4 and vimentin.Main Outcome Measure(s): The presence of spermatogonia.Result(s): Massive fibrosis and hyalinization were observed in all men with KS. Spermatogonia were observed in 4 of 22 men with KS, with differentiation up to the spermatocyte level in 2 of them.Conclusion(s): A few men with KS, having no spermatozoa after testicular sperm extraction, still had few spermatogonia. These patients may eventually benefit from in vitro maturation using spermatogonial stem cells. The adult KS population can thus be divided into three subgroups: one subgroup showing focal spermatogenesis, a second having spermatogonia, and a third group in which no germ cells can be recovered. Further research is necessary to unravel the mechanism leading to these different patterns in patients with KS.

Elective single embryo transfer and perinatal outcomes: a systematic review and meta-analysis

Rosheen Grady, Nika Alavi, Rachel Vale, Mohammad Khandwala, Sarah D. McDonald — 2011-12-15

Objective: To determine whether elective single embryo transfer (eSET) lowers the risk of poor perinatal outcomes associated with IVF, when [1] compared with double embryo transfer (DET) or multiple embryo transfer (MET), and separately, [2] compared with spontaneous conceptions.Design: Systematic review and meta-analysis.Setting: Centers for reproductive care.Patient(s): Infertility patients.Intervention(s): MEDLINE, Embase, and bibliographies were searched for the period 1978–2011. Two reviewers independently assessed titles, abstracts, and full studies, extracted data, and assessed quality. Dichotomous data were pooled using relative risks and continuous data with mean differences using a random effects model. Randomized controlled trials (RCTs), case–control studies, and cohort studies that examined any of the primary or secondary outcomes in singleton, twin, or multiple-order infants conceived by eSET as compared with [1] those conceived by DET or MET or [2] spontaneously conceived singleton gestations were included.Main Outcome Measure(s): Primary outcomes were preterm birth (PTB, <37 weeks’ gestation) and low birth weight (LBW, <2,500 g).Result(s): Sixteen studies were included (eight RCTs, eight cohort studies). Compared with DET-conceived infants, eSET-conceived singletons were less likely to be born either preterm (RCT-based relative risk [RR] 0.37, 95% confidence interval [CI] 0.25–0.55) or with LBW (RCT-based RR 0.25, 95% CI 0.15–0.45; cohort study RR 0.51, 95% CI 0.29–0.91). However, compared with spontaneously conceived singletons, eSET gestations had higher risks of PTB (RR 2.13, 95% CI 1.26–3.61), placenta previa (RR 6.02, 95% CI 2.79–13.01), gestational diabetes (RR 1.69, 95% CI 1.19–2.42), and ectopic pregnancy (RR 6.40, 95% CI 4.38–9.35).Conclusion(s): Elective single embryo transfer is associated with decreased risks of PTB and LBW compared with DET but higher risks of PTB compared with spontaneously conceived singletons.

Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging

Shu Hashimoto, Nobuhiro Kato, Kazuhiro Saeki, Yoshiharu Morimoto — 2012-01-03

Objective: To assess the developmental kinetics of human embryos and their ability to develop to morphologically normal blastocysts.Design: Experimental study on human embryos donated for research using a time-lapse imaging system based on individual embryo culture in poly(dimethylsiloxane) microwells and monitored using a microscope inside the incubator.Setting: Private fertility clinic.Patient(s): Surplus embryos donated by couples after undergoing fertility treatment.Intervention(s): None.Main Outcome Measure(s): Blastocyst score and times required from beginning to completion of the second and third mitotic divisions.Result(s): The time required for completion of the second division (the three- to four-cell stage) was shorter in embryos that developed to high-scoring blastocysts (0.7 hours, n = 17) than in those forming low-scoring blastocysts (3.7 hours, n = 24). Similarly, the mean time required to completion of the third division (five- to eight-cell stage) was also significantly shorter in embryos forming high-scoring blastocysts (5.7 hours) than among those forming low-scoring blastocysts (16.9 hours).Conclusion(s): Individual embryos with the potential to develop to high-scoring blastocysts could be selected at 2–3 days of culture using this system by examining the times required to complete the second and third mitotic divisions.

Developmental potential of embryos from intracytoplasmic sperm injection cycles containing fragmented oocytes

2011-12-08

Objective: To determine the incidence of fragmented oocytes in intracytoplasmic sperm injection (ICSI) cycles, describe the developmental potential of their sibling oocytes, and define clinical outcomes from affected cycles.Design: Case-control study.Setting: Academic medical center.Patient(s): All ICSI cycles from January 2006 to December 2010 (n = 2,844) were reviewed for the presence of fragmented oocytes at cumulus stripping or fertilization check (n = 93). Sibling oocytes and corresponding embryos from index cycles were compared with matched control cycles without fragmented oocytes.Intervention(s): None.Main Outcome Measure(s): Cycle characteristics, embryo quality, and pregnancy rates per retrieval.Result(s): The incidence of ICSI cycles containing at least one fragmented oocyte was 3.3% (93/2,844). Twelve patients were represented more than once in these 93 index cycles. Only the first cycles (n = 81) were included, of which 28 contained fragmented oocytes at cumulus stripping, 48 at fertilization check, and five at both. Compared with matched controls, index cycles had fewer good-quality embryos available for transfer (18.8% vs. 32.1%) and significantly lower rates of implantation (20.3% vs. 32.7%), clinical pregnancy (33.3% vs. 58.0%), and ongoing delivery (29.6% vs. 49.4%). The cumulative ongoing delivered rate was also significantly lower for index cycles (32.1% vs. 55.6%), with no difference in the percentage of cycles with cryopreserved embryos remaining at study conclusion (13.5% vs. 23.5%).Conclusion(s): Cohorts containing fragmented oocytes have decreased developmental potential. The biologic mechanisms underlying this occurrence merit further investigation, and patient counseling should reflect the possible decreased success rates associated with this aberrant developmental pattern.

Vaginal (Crinone 8%) gel vs. intramuscular progesterone in oil for luteal phase support in in vitro fertilization: a large prospective trial

2011-12-20

Objective: To compare the efficacy of intravaginal and IMP for luteal phase support in IVF cycles.Design: Prospective trial.Setting: Tertiary care private practice.Patient(s): Women 25–44 years old with infertility necessitating treatment with IVF. From April 1, 2008–April 1, 2009, 511 consecutive patients were enrolled; 474 completed participation, and 37 were excluded for no autologous ET (freeze all, donor recipients, failed fertilization/cleavage). There were no demographic differences between the two treatment groups.Intervention(s): Luteal phase support using either Crinone or P in oil starting 2 days following oocyte retrieval.Main Outcome Measure(s): Pregnancy and delivery rates stratified by patient age.Result(s): Overall, patients who received vaginal P had higher pregnancy (70.9% vs. 64.2%) and delivery (51.7% vs. 45.4%) rates than did patients who received IMP. Patients <35 who received vaginal P had significantly higher delivery rates (65.7% vs. 51.1%) than did patients who received IMP. There were no differences, regardless of age, in the rates of biochemical pregnancy, miscarriage, or ectopics.Conclusion(s): In younger patients undergoing IVF, support of the luteal phase with Crinone produces significantly higher pregnancy rates than does IMP. Crinone and IMP appear to be equally efficacious in the older patient.

Effect of maternal height and weight on risk of preterm birth in singleton and twin births resulting from in vitro fertilization: a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System

Richard P. Dickey, Xu Xiong, Rebekah E. Gee, Gabriella Pridjian — 2011-12-12

Objective: To examine the effect of height, weight, and body mass index (BMI) on the risk of preterm birth of singleton and twin pregnancies conceived by vitro fertilization (IVF).Design: Retrospective cohort study using 2006–2008 data from the Society for Reproductive Technology Clinic Outcome Reporting System (SART CORS).Setting: SART-associated assisted reproductive technology programs.Patient(s): 56,556 singleton and 23,804 twin live births resulting from fresh nondonor IVF cycles.Intervention(s): None.Main Outcome Measure(s): Rates of very early preterm (VEPTB; <28 weeks), very preterm (VPTB; <32 weeks), and preterm birth (<37 weeks) births.Result(s): In both singleton and twin births, increased maternal height was associated with a decreased risk of preterm birth. Maternal overweight and obesity were associated with significantly increased risk of VEPTB and VPTB in twin pregnancies. For very obese women (BMI > 35 kg/m2) twins were associated with a threefold increased risk of VEPTB (6.1% vs. 2.0%) and a twofold increased risk of VPTB (11.5% vs. 5.9%) compared with women of normal weight (BMI 18.4–24.9 kg/m2).Conclusion(s): Obesity and short stature significantly increase the risk of VEPTB and VPTB in twins conceived by IVF.

A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss

2011-12-22

Objective: To determine the cost-effectiveness of medical and surgical management of early pregnancy loss.Design: Analyses of cost, effectiveness, and incremental cost-effectiveness ratios and utilities of a multicenter trial with 652 women with first-trimester pregnancy failure randomized to medical or surgical management.Setting: Analysis of data from a multicenter trial.Patient(s): Secondary analysis of a multicenter trial.Intervention(s): Cost-effectiveness analysis.Main Outcome Measure(s): Cost and effectiveness of competing treatment strategies.Result(s): Cost analysis of treatment demonstrates an increased cost of US$336 for 13% increased efficacy of surgical management. This analysis was sensitive to the probability of an extra office visit, the cost of the visit, and the probability of success. When the surgical arm is divided into outpatient manual vacuum aspiration (MVA) versus inpatient electric vacuum aspiration (EVA), there is an increased cost of $745 for EVA but a decreased cost of $202 for MVA compared with medical management. In general, MVA was found to be more cost-effective than medical management. For treatment of incomplete or inevitable abortion, medical management was found to be less costly and more efficacious. Utilities studies demonstrated that a patient would need to prefer surgery 14% less than medication for its treatment efficacy to be outweighed by the desire to avoid surgery.Conclusion(s): Surgical or medical management of early pregnancy failure can be cost effective, depending on the circumstances. Surgery is cost effective and more efficacious when performed in an outpatient setting. For incomplete or inevitable abortion, medical management is cost effective and more efficacious.

Antitrophoblast antibodies are associated with recurrent miscarriages

2011-12-09

Objective: To investigate whether antitrophoblast antibodies are associated with unexplained recurrent miscarriages, we used choriocarcinoma cells JEG-3, since these cells are negative for class I and II antigens, but they do express HLA-G, resembling an antigen expression of endovascular and interstitial trophoblasts.Design: Case-control study.Setting: Academic research center.Patient(s): One hundred ninety-four patients with two or more consecutive, idiopathic recurrent miscarriages (RM; <20 weeks of gestation) were compared with 110 controls with normal pregnancies and without pregnancy complications.Intervention(s): Anti-JEG-3 reactivities were measured by using flow cytometry and comparisons with two in-house standards antibody samples of low and high reactivity.Main Outcome Measure(s): Anti-JEG-3 reactivities above the 95% confidence interval of controls were defined as positive.Result(s): Sera of RM patients reacted significantly stronger with JEG-3 cells than that of controls. In addition, RM patients significantly more often had positive anti-JEG-3 reactivities (17.5%) than controls 5%. This difference was markedly increased with a subgroup of 80 RM patients who had three or more miscarriages, as 27 of these women (34%) were anti-JEG-3 positive.Conclusion(s): Antitrophoblast antibodies show significantly more mean channel shift reactivities, and positive reactivities are significantly more prevalent in RM patients as compared with controls. Such antibodies may be involved in mechanisms affecting pregnancies.

Deep infiltrating endometriosis is a determinant factor of cumulative pregnancy rate after intracytoplasmic sperm injection/in vitro fertilization cycles in patients with endometriomas

2011-12-16

Objective: To evaluate the cumulative pregnancy rate (CPR) per patient after in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) cycles in patients with endometriomas and to evaluate the determinant factors of CPR per patient.Design: Retrospective study from January 2007 to October 2008.Setting: Tertiary care university hospital.Patient(s): 103 patients who had undergone IVF treatment, comprising isolated endometriomas (n = 30) and endometriomas with associated deep infiltrating endometriosis (DIE) (n = 73).Intervention(s): None.Main Outcome Measure(s): Clinical pregnancy rate after IVF-ICSI cycle.Result(s): The total number of cycles was 162, and the median number of cycles per patient was 1 (1 to 5). Fifty-eight women (56.3%) became pregnant. The total number of endometriomas and size of the largest endometrioma and bilateral endometriomas had no impact on the CPR per patient. Using multivariable analysis, the associated DIE and antimüllerian hormone serum level (≤1 ng/mL) were independent factors associated with a decrease in the pregnancy rate per patient. Overall, the CPR per patient was 73.7%, and it increased until the third cycle with no benefit for additional cycles. The CPR per patient for women with isolated endometriomas and women with endometriomas and associated DIE was 82.5% and 69.4%, respectively.Conclusion(s): Associated DIE has a negative impact on assisted reproduction results in patients with endometriomas. Moreover, our data show that after three IVF-ICSI cycles the CPR per patient is not improved and that surgery should be considered.

Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations

Brett McKinnon, Nick A. Bersinger, Carlos Wotzkow, Michael D. Mueller — 2011-12-12

Objective: To assess the relationship between endometriotic lesions with associated nerve fibers with both pain and peritoneal fluid (PF) cytokine concentrations based on lesion location.Design: An observational study.Setting: University hospital.Patient(s): Premenopausal women undergoing laparoscopy.Intervention(s): The pain experienced by patients was recorded before surgery and ectopic endometrial tissue excised and matching PF collected during laparoscopy. Immunohistochemistry was performed on endometriotic tissue sections to identify nerve fibers and PF cytokine concentrations determined.Main Outcome Measure(s): The pain experienced by women with endometriosis, the lesion locations, and the prevalence and proximity of nerve fibers to endometriotic lesions, as well as the PF concentrations of multiple cytokines.Result(s): Lesions from the rectovaginal septum were significantly more likely to be associated with a nerve fiber and report more menstrual pain than lesions from other regions. The PF glycodelin concentrations were also significantly higher in samples with an endometriotic-associated nerve. In peritoneal endometriotic lesions significantly more menstrual pain was reported when endometriotic lesions were associated with nerve fibers, although no difference was observed between the cytokine concentrations. Ovarian endometriotic lesions were rarely associated with nerve fibers.Conclusion(s): The presence of endometriosis-associated nerve fibers appear to be related to both the pain experienced by women with endometriosis and the concentration of PF cytokines; however, this association varies with the lesion location.

Female cancer survivors are low responders and have reduced success compared with other patients undergoing assisted reproductive technologies

Sara E. Barton, Stacey A. Missmer, Katharine F. Berry, Elizabeth S. Ginsburg — 2011-12-16

Objective: To investigate the effect of prior chemotherapy and radiation on assisted reproductive technology (ART) outcomes.Design: Retrospective cohort study.Setting: University-based infertility clinic.Patient(s): Female cancer survivors who had received chemotherapy or radiation and all other women undergoing first-fresh IVF/intracytoplasmic sperm injection (ICSI) cycles.Intervention(s): Survivors’ ART outcomes were compared with all women undergoing first-fresh IVF/ICSI cycles and those with male-factor infertility only. Multivariate logistic and Poisson regression analyses were used to estimate the effect of cancer therapy on ART outcomes.Main Outcomes Measure(s): Number of oocytes retrieved and embryos obtained; odds of cycle cancelation, clinical pregnancy, and live birth.Result(s): Compared with others undergoing IVF/ICSI, survivors had significantly fewer oocytes retrieved and embryos available for transfer. In addition, survivors were significantly more likely to be canceled (odds ratio [OR] 5.60, 95% CI 2.94–10.66) and had lower pregnancy and live birth rates (OR 0.30, 95% CI 0.13–0.68; and OR 0.27, 95% CI 0.10–0.69; respectively). Odds ratios were stronger when the comparison group was restricted to those with male-factor infertility only.Conclusion(s): Women who have received systemic therapy for malignancy should be considered to be low responders and counseled that their per-cycle live birth rate is lower than that of their peers. These data strongly support offering fertility preservation before cancer therapy when possible.

Live birth after ovarian tissue autotransplantation following overnight transportation before cryopreservation

2011-12-19

Objective: To describe the first live birth after transplantation of ovarian tissue following overnight transportation of the tissue before freezing.Design: Technical note.Setting: University department of obstetrics and gynecology.Patient(s): A 25-year-old cancer survivor with previous Hodgkin disease and relapse.Intervention(s): The ovarian tissue was kept cool for >20 hours in a special transport medium and a special cooling device before it was cryopreserved. After premature ovarian failure due to preconditioning chemotherapy for bone marrow transplantation, the cryopreserved ovarian tissue was transplanted orthotopically.Main Outcome Measure(s): Resumption of ovarian function after transplantation, recovery of fertility, and pregnancy.Result(s): Ovarian function returned in the patient 3 months after transplantation, as shown by follicle development and estrogen production. During the fifth menstrual cycle, mild stimulation with FSH was initiated in accordance with a low-dose protocol. When ultrasonography revealed a follicle 18–20 mm in size in the ovarian graft, hCG was added and the patient had sexual intercourse at the optimal time point. On day 14 of the luteal phase, hCG concentration and vaginal echography confirmed a viable intrauterine pregnancy, which resulted in a healthy live birth.Conclusion(s): Overnight transportation of ovarian tissue appears to be possible in combination with appropriate transportation logistics. However, further investigations are needed before this procedure can be offered as a chance for women to preserve fertility independently of direct access to a tissue-processing bank.

Variants of the WNT7A gene in Chinese patients with müllerian duct abnormalities

2011-12-19

Objective: To search for WNT7A gene mutations in a cohort of 191 Chinese Han patients with müllerian duct abnormalities (MDAs).Design: Phenotypic and mutational study.Setting: University hospital.Patient(s): A total of 191 Chinese Han patients with MDAs and 192 healthy control individuals.Intervention(s): Genomic DNA extracted from blood samples, all coding regions amplified by polymerase chain reaction (PCR) then directly sequenced to screen variants.Main Outcome Measure(s): Not applicable.Result(s): The sequence analysis revealed one novel synonymous variant and three known single-nucleotide polymorphisms (SNPs).Conclusion(s): The results indicate that mutations in the coding sequence of WNT7A are not responsible for müllerian duct abnormalities in the Chinese population.

Origins and rates of aneuploidy in human blastomeres

2011-12-22

Objective: To characterize chromosomal error types and parental origin of aneuploidy in cleavage-stage embryos using an informatics-based technique that enables the elucidation of aneuploidy-causing mechanisms.Design: Analysis of blastomeres biopsied from cleavage-stage embryos for preimplantation genetic screening during IVF.Setting: Laboratory.Patient(s): Couples undergoing IVF treatment.Intervention(s): Two hundred seventy-four blastomeres were subjected to array-based genotyping and informatics-based techniques to characterize chromosomal error types and parental origin of aneuploidy across all 24 chromosomes.Main Outcome Measure(s): Chromosomal error types (monosomy vs. trisomy; mitotic vs. meiotic) and parental origin (maternal vs. paternal).Result(s): The rate of maternal meiotic trisomy rose significantly with age, whereas other types of trisomy showed no correlation with age. Trisomies were mostly maternal in origin, whereas paternal and maternal monosomies were roughly equal in frequency. No examples of paternal meiotic trisomy were observed. Segmental error rates were found to be independent of maternal age.Conclusion(s): All types of aneuploidy that rose with increasing maternal age can be attributed to disjunction errors during meiosis of the oocyte. Chromosome gains were predominantly maternal in origin and occurred during meiosis, whereas chromosome losses were not biased in terms of parental origin of the chromosome. The ability to determine the parental origin for each chromosome, as well as being able to detect whether multiple homologs from a single parent were present, allowed greater insights into the origin of aneuploidy.

Should TSPYL1 mutation screening be included in routine diagnostics of male idiopathic infertility?

2011-12-02

Objective: To investigate a putative role of TSPYL1 in male idiopathic infertility.Design: Clinical article.Setting: University hospital.Patient(s): A total of 104 infertile men were selected with idiopathic nonobstructive azoospermia, cryptozoospermia, oligozoospermia, oligonecrozoospermia, and oligoasthenoteratozoospermia (OAT) syndrome, along with a control group of 106 men with proven paternity.Intervention(s): Mutation screening of the coding region and parts of the 5′ and 3′ untranslated regions of the TSPYL1 gene was performed by polymerase chain reaction and sequencing.Main Outcome Measure(s): Occurrence of TSPYL1 single-nucleotide polymorphisms (SNPs) and mutations.Result(s): In these cohorts, eight known TSPYL1 SNPs were identified, none of which was significantly associated with male infertility. Two potentially disease-causing variants were detected in the infertile cohort: one man with azoospermia was found to be heterozygous for the novel TSPYL1 variant c.419C>G (p.Ser140Cys), and the rare substitution c.1098C>A (p.Phe366Leu) was identified in a man with OAT syndrome in the heterozygous state. Additionally, one fertile man was found to be heterozygous for the rare variant c.487G>A (p.Val163Ile). In silico analyses predicted a nonpathogenic effect for all amino acid exchanges, although protein features might be affected by p.Ser140Cys and p.Phe366Leu, respectively.Conclusion(s): Mutations in the TSPYL1 gene do not seem to play a major role in the pathogenesis of idiopathic male infertility, and mutation screening of the TSPYL1 gene can currently not be recommended in routine diagnostics of idiopathic male infertility.

Knowledge and attitudes regarding expanded genetic carrier screening among women’s healthcare providers

Kaylene Ready, Imran S. Haque, Balaji S. Srinivasan, John R. Marshall — 2011-12-02

Objective: To determine women’s healthcare providers’ knowledge and attitudes regarding genetic disorders and expanded genetic screening.Design: Survey of American Society for Reproductive Medicine 2010 and American College of Obstetricians and Gynecologists 2011 Annual Meeting attendees. The survey included 60 items (12 demographic, 10 knowledge, and 38 attitude). Attitudes were assessed with a 5-point Likert scale. Chi-square or t tests determined significance.Setting: American Society for Reproductive Medicine 2010 and American College of Obstetricians and Gynecologists 2011 Annual Meeting.Patient(s): A total of 203 participants completed the survey. Of these, 48% were male, 61% were physicians, 73% were Caucasian, and 42% were aged 35–50 years.Intervention(s): None.Main Outcome Measure(s): None.Result(s): Physicians had better knowledge scores than other participants (87% vs. 79%). Knowledge was not influenced by prior personal/family experience with genetic screening. Fewer correct answers were observed for the probability of a positive test (65.2%), the risk of transmitting a gene mutation (62.2%), and the risk of having an affected child (56.2%). Very few participants (18.3%) disagreed with the notion of carrier screening as socially responsible behavior. Some had concerns about test result confidentiality (40.1%) and resulting insurance rate increases (37.0%). Assuming equal costs, most participants preferred to be tested for a larger number of diseases (77.7%) and believed posttest counseling to be helpful (83.7%).Conclusion(s): Women’s healthcare providers generally had good knowledge and positive attitudes about genetic disorders and expanded genetic screening. Specific misperceptions, both medical and legal, require education.

Sex-related differences in association of oxidative stress status with coronary artery disease

2011-12-23

Objective: To assess oxidative stress status in coronary artery disease (CAD) patients according to gender.Design: Case-controlled, observational, retrospective study.Setting: Clinical and research center.Patient(s): A total of 55 postmenopausal women and 108 men (mean age: 66 ± 9 years), including 72 patients with angiographically proven CAD (CAD(+), 19 women) and a group of 91 age-matched controls (CAD(−), 36 women).Intervention(s): None.Main Outcome Measure(s): Oxidant/antioxidant balance as a global index (oxidative index) obtained using two commercial assays (d-ROMs and OXY Adsorbent Test, respectively) for estimation of levels of reactive oxygen metabolites and total antioxidant status.Result(s): There was a statistically significant difference in oxidative stress status between men and women who were CAD(−) (−0.424 ± 1.3 vs. 0.64 ± 1.1 arbitrary units, respectively), but the CAD(+) women had oxidative stress levels almost three times those of the CAD(+) men (2.45 ± 2.5 vs. 0.9 ± 1.6 arbitrary units, respectively). After adjustment in the multivariate model, age and oxidative stress status in women and diabetes and age in men remained as statistically significant predictors of positive CAD findings.Conclusion(s): Oxidative stress status was a powerful predictor of CAD in women. This result may have important implications for the differences between sexes in CAD physiopathology.

Childless women’s knowledge of fertility and assisted human reproduction: identifying the gaps

Judith C. Daniluk, Emily Koert, Anthony Cheung — 2011-12-22

Objective: To determine the knowledge about fertility and assisted human reproduction (AHR) treatments of a large sample of childless women.Design: Self-report questionnaire comprising two self-ratings of current fertility and AHR knowledge, and 16 knowledge questions related to fertility and AHR.Setting: Online.Patient(s): A total of 3,345 childless women between the ages of 20 and 50.Intervention(s): None.Main Outcome Measure(s): Knowledge of fertility and AHR.Result(s): The majority of participants rated themselves as having some knowledge or being fairly knowledgeable about fertility and AHR. However, on the 16 knowledge questions, overall knowledge was low, with 50% or more of the sample answering only 6 of 16 questions correctly.Conclusion(s): The data suggest that the women in the study have no coherent body of knowledge regarding age-related fertility and AHR treatment options. With an increasing number of women electing to delay childbearing, there is a critical need for public education regarding age-related fertility declines and the availability, costs, and limitations of AHR. This study offers important mental health contributions to infertility prevention and public health education efforts.

Informing egg donors of the potential for embryonic research: a survey of consent forms from U.S. in vitro fertilization clinics

Gerald Owen Schaefer, Ninet Sinaii, Christine Grady — 2011-12-26

Objective: To understand whether and to what extent U.S. IVF clinics inform egg donors that resultant embryos initially intended to be implanted for reproductive purposes may in fact be used for research instead.Design: Four hundred seventy U.S. IVF clinics were asked to respond to a questionnaire and provide a copy of the egg donor consent form(s) used at the clinic.Setting: Four hundred seventy U.S. IVF clinics listed in a Centers for Disease Control and Prevention database; only forms from clinics that both accepted donor eggs and provided excess embryos for research were analyzed for content.Patient(s): Not applicable.Intervention(s): Not applicable.Main Outcome Measure(s): Responses to the questionnaire, demographic data from a Centers for Disease Control and Prevention database, and the content of egg donor consent forms.Result(s): Of 222 U.S. IVF clinics that responded to our query, 100 clinics both accepted donor eggs and provided some excess embryos for research. We received 66 consent forms from these 100 clinics, which showed that although most egg donor consent forms inform donors that they will not have control over embryos resulting from their eggs, 30% inform them that some embryos may be used for research, and even fewer mention stem cell research.Conclusion(s): Egg donors in the United States, including some who may have a moral objection to research and stem cell research, are not being informed that embryos created with their donated eggs may in fact be used for these purposes. This can be corrected with the inclusion of succinct, nontechnical language in egg donor consent forms.

Male fertility: psychiatric considerations

Elise Hall, Vivien K. Burt — 2011-12-16

Objective: To examine: 1) current knowledge on normal biologic variation of seminal parameters; 2) how stress and psychological factors affect sperm quality in fertile and infertile males; and 3) how mental illness and psychopharmacologic agents can affect male fertility.Design: English-language Medline, Embase, and Psycinfo were searched for relevant publications (from 1970 to January 2011) for systematic review.Setting: None.Patient(s): None.Intervention(s): None.Main Outcome Measure(s): Possible effects of stress, mood, and psychotropic medications on male factor fertility.Result(s): Male-factor infertility is influenced by myriad factors (obesity, tobacco, etc.). Stress alone may reduce testosterone levels and spermatogenesis. Infertility assessment and treatment can lead to distress and negatively affect sperm samples. Available research has failed to control for potentially confounding variables.Conclusion(s): Although some trends have been identified, larger-scale studies that adequately control all confounding variables are needed before conclusions can be made about the relationship between stress, psychotropic agents, and male infertility.

Impact of infertility regimens on breast cancer cells: follicle-stimulating hormone and luteinizing hormone lack a direct effect on breast cell proliferation in vitro

2011-12-20

Objective: To examine the impact of hormones used for controlled ovarian hyperstimulation (COH) on normal and malignant breast cell growth and proliferation.Design: In vitro study of cultured normal and malignant breast cell lines.Setting: Academic medical center.Patient(s): None.Intervention(s): Normal and malignant breast cell lines cultured in two- and three-dimensional (2D and 3D) systems and treated with follicle-stimulating hormone (FSH), luteinizing hormone (LH), or FSH with LH or human chorionic gonadotropin (hCG).Main Outcome Measure(s): Effects of treatment on cell proliferation in 2D culture using the MTS assay and on colony growth in 3D culture.Result(s): Compared with untreated cells, normal MCF-10A cells showed a decrease in proliferation and colony size when exposed to a combination of FSH and hCG. The HCC 1937 cells treated with FSH and LH also showed a decrease in colony growth but no change in proliferation. None of the treatments had an effect on the proliferation or colony size of the MCF-7 cells.Conclusion(s): Follicle-stimulating hormone, LH, and hCG do not appear to cause an increase in cell proliferation or colony growth in either normal or malignant mammary epithelial cell lines. The potential risk for mammary cell transformation associated with these agents may be related to indirect endocrine effects on breast cell physiology.

Immunization of male mice with B-cell epitopes in transmembrane domains of CatSper1 inhibits fertility

Honggang Li, Xiaofang Ding, Cuicui Guo, Huangtao Guan, Chengliang Xiong — 2011-12-26

Objective: To evaluate the contraceptive ability of two B-cell epitopes in CatSper1.Design: In vivo study with mice.Setting: University laboratory animal service center.Animal(s): BALB/c mice.Intervention(s): Two predicted B-cell epitopes in the extracellular part of transmembrane domains and pore region of CatSper1 were synthesized to immunize male mice.Main Outcome Measure(s): Fertility, epididymal sperm function, and the presence of specific antibody in immunized males were investigated.Result(s): Significant reduction of fertility was observed in mating trial with no evident systemic illness or abnormal mating behavior. Epididymal sperm of epitope-immunized males exhibited impaired ability to fertilize eggs in vitro, and showed sperm agglutination in some animals, while presenting no changes in sperm viability or progressive motility. High titer of antibodies was induced in the sera, and the antibodies’ specificity was confirmed. The binding of the antibodies to epididymal sperm of epitope-immunized males was observed.Conclusion(s): CatSper members could be the effective and viable targets for immunocontraception. These two epitopes in CatSper1 share high identity between mouse and human and may be effective for fertility regulation in humans.

Fertilization outcome could be regulated by binding of oviductal plasminogen to oocytes and by releasing of plasminogen activators during interplay between gametes

2011-12-19

Objective: To detect plasminogen and plasminogen activators (PA) in oviduct and oocytes and to clarify the role of the plasminogen/plasmin system on mammalian fertilization.Design: Experimental prospective study.Setting: Mammalian reproduction research laboratory.Animal(s): Oviducts and ovaries from porcine and bovine females were collected at slaughterhouse. A total of 52 oviducts and 2,292 oocytes were used. Boar and bull ejaculated spermatozoa were also used.Intervention(s): Plasminogen concentration in oviductal fluid (OF) through the cycle was measured. Immunolocalization of plasminogen and PAs in oocytes was carried out before and after fertilization. Porcine and bovine oocytes were in vitro fertilized, with plasminogen and plasmin added to the culture medium at different concentrations.Main Outcome Measure(s): Plasminogen concentration in OF. Plasminogen and PAs immunolocalization in oocytes. Penetration and monospermy rates, number of spermatozoa in the ooplasma and on the zona pellucida (ZP) after IVF.Result(s): Oviductal fluid contains about 92 μg/mL of plasminogen. The mature oocyte shows immunoreactivity toward plasminogen and toward PAs on its oolemma and ZP. After fertilization, plasminogen and PAs immunolabeling decreases in the oocyte, suggesting its conversion into plasmin. When exogenous plasminogen is added to the IVF medium, sperm entry into the oocyte is hampered, suggesting that the role of plasminogen activation during fertilization is to reduce the number of (or to select) penetrating spermatozoa.Conclusion(s): The plasminogen/plasmin system is activated during gamete interaction and regulates the sperm entry into the oocyte.

Arteriolar insulin resistance in a rat model of polycystic ovary syndrome

2011-12-12

Objective: To investigate the vascular dysfunction caused by insulin resistance in polycystic ovary syndrome (PCOS) and the effectiveness of vitamin D in an animal model.Design: Controlled experimental animal study.Setting: Animal laboratory at a university research institute.Animal(s): Thirty female Wistar rats.Intervention(s): Rats were divided into groups at age 21–28 weeks. Twenty of them were subjected to dihydrotestosterone (DHT) treatment (83 μg/d); ten of them also received parallel vitamin D treatment (120 ng/100 g/wk). Oral glucose tolerance tests with insulin level measurements were performed. Gracilis arterioles were tested for their contractility as well as their nitric oxide (NO)–dependent and insulin-induced dilation using pressure arteriography.Main Outcome Measure(s): Several physiologic parameters, glucose metabolism, and pressure arteriography.Result(s): DHT treatment increased the passive diameter of resistance arterioles, lowered norepinephrine-induced contraction (30.1 ± 4.7% vs. 8.7 ± 3.6%) and reduced acetylcholine-induced (122.0 ± 2.9% vs. 48.0 ± 1.4%) and insulin-induced (at 30 mU/mL: 21.7 ± 5.3 vs. 9.8 ± 5.6%) dilation. Vitamin D treatment restored insulin relaxation and norepinephrine-induced contractility; in contrast, it failed to alter NO-dependent relaxation.Conclusion(s): In DHT-treated rats, in addition to metabolically proven insulin resistance, decreased insulin-induced vasorelaxation was observed and was improved by vitamin D treatment without affecting NO-dependent relaxation. The reduction in insulin-induced dilation of arterioles is an important as yet undescribed pathway of vascular damage in PCOS and might explain the clinical effectiveness of vitamin D treatment.

Androstenedione induces abnormalities in morphology and function of developing oocytes, which impairs oocyte meiotic competence

2012-02-01

Objective: To obtain insight into the effects of androstenedione on ovarian folliculogenesis and oogenesis.Design: Experimental study.Setting: St. Marianna University School of Medicine.Animal(s): Prepubertal (14-day-old) BDF1 female mice.Intervention(s): Early secondary follicles were isolated from the ovaries and were cultured individually in vitro with or without androstenedione (10−11 to 10−5 M) for 12 days. Thereafter, the follicles were treated with hCG and epidermal growth factor (EGF).Main Outcome Measure(s): Diameters and morphology of follicles and oocytes; E2 and P secretion; and chromatin configuration and expression of growth differentiation factor 9 (GDF9) in oocytes were examined.Result(s): Early secondary follicles developed to the preovulatory stage. Androstenedione treatments increased the follicle diameters, reduced survival rates of follicles, and promoted the formation of follicles with abnormal morphology, including misshapen oocyte. The secretion of E2 and P was significantly higher in androstenedione-exposed follicles. Androstenedione prevented the alteration in chromatin configuration and reduced oocyte GDF9 expression. When follicles cultured with androstenedione were treated with hCG and EGF, the first polar body exclusion, chromosome alignment on metaphase plate, and spindle assembly were inhibited in the oocytes.Conclusion(s): These results demonstrate that excess androgen induces abnormalities in the morphology and function of developing oocytes, which impairs oocyte meiotic competence.

Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic stromal cells in spheroid culture

2011-11-30

Objective: To determine the effect of dienogest (DNG) on the expression of aromatase and cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in human endometriotic stromal cells (ESCs).Design: Experimental study in vitro.Setting: University hospital.Patient(s): Seventeen patients with ovarian endometrioma.Intervention(s): ESCs from chocolate cyst linings of ovaries were treated with DNG.Main Outcome Measure(s): Expression of aromatase and COX-2 evaluated in spheroid cultures of human ESCs by real-time quantitative polymerase chain-reaction and immunocytochemistry, production of PGE2 quantified by enzyme-linked immunosorbent assay (ELISA), and nuclear factor kappa B (NF-κB) DNA-binding examined by ELISA and immunocytochemistry.Result(s): The pharmaceutical actions of DNG on the expression of aromatase and COX-2 and the production of PGE2 were examined using spheroid cultures of human ESCs. More aromatase, COX-2, and PGE2 were expressed in spheroid cultures than in conventional ESCs monolayers. In the spheroid cultures, DNG (10−7 M) and progesterone (10−7 M) inhibited the expression of aromatase, COX-2, and PGE2. DNG also inhibited NF-κB DNA-binding activity and reduced the immunocytochemical protein expression of aromatase, COX-2, and NF-κB p50 nuclear localization.Conclusion(s): Because DNG inhibits aromatase and COX-2 expression as well as PGE2 production in ESCs, these pharmacologic features might contribute to a therapeutic effect of DNG on endometriosis.

Estriol administration modulates luteinizing hormone secretion in women with functional hypothalamic amenorrhea

2011-12-02

Objective: To evaluate the influence of estriol administration on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA).Design: Controlled clinical study.Setting: Patients with FHA in a clinical research environment.Patient(s): Twelve hypogonadotropic patients affected by FHA.Intervention(s): Pulsatility study of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a gonadotropin-releasing hormone (GnRH) test (10 μg in bolus) at baseline condition and after 8 weeks of therapy with 2 mg/day of estriol.Main Outcome Measure(s): Measurements of plasma LH, FSH, estradiol (E2), androstenedione (A), 17α-hydroxyprogesterone (17-OHP), cortisol, androstenedione (A), testosterone (T), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and insulin, and pulse detection.Result(s): After treatment, the FHA patients showed a statistically significant increase of LH plasma levels (from 0.7 ± 0.1 mIU/mL to 3.5 ± 0.3 mIU/mL) and a statistically significant increase of LH pulse amplitude with no changes in LH pulse frequency. In addition, the LH response to the GnRH bolus was a statistically significant increase.Conclusion(s): Estriol administration induced the increase of LH plasma levels in FHA and improved GnRH-induced LH secretion. These findings suggest that estriol administration modulates the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of LH synthesis and secretion in hypogonadotropic patients with FHA.

Effects of transdermal testosterone on natriuretic peptide levels in women: a randomized placebo-controlled pilot study

2011-12-02

Objective: To investigate whether testosterone administration alters natriuretic peptide levels in women.Design: Three-month, double-blind, randomized, placebo-controlled study.Setting: Clinical research center.Patient(s): Fifty-one women with hypoandrogenemia due to hypopituitarism.Intervention(s): Transdermal testosterone (300 μg daily) or placebo patch.Main Outcome Measure(s): N-Terminal pro–B-type natriuretic peptide (NT-proBNP) levels.Result(s): NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months. The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model assessment of insulin resistance. Change in NT-proBNP over 3 months was inversely associated with change in free testosterone levels.Conclusion(s): Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system.Clinical Trials Registration Number: NCT00027430.

Cross-sectional analysis of the effects of age on the hormonal, metabolic, and ultrasonographic features and the prevalence of the different phenotypes of polycystic ovary syndrome

2011-12-22

Objective: To assess the effects of age on the hormonal, metabolic, and ultrasonographic features of polycystic ovary syndrome (PCOS).Design: Observational study.Setting: University department of obstetrics and gynecology.Patient(s): Patients with PCOS (n = 1,212) and healthy women (n = 254).Intervention(s): None.Main Outcome Measure(s): Differences in the hormonal, metabolic, and ultrasonographic features of PCOS between age groups.Result(s): A progressive decline in circulating androgens was observed with advancing age. Patients 21–30 years old had lower plasma glucose and insulin levels, lower area under the oral glucose tolerance test curve and lower homeostasis model assessment of insulin resistance index, and higher glucose/insulin and quantitative insulin sensitivity check index than patients 31–39 years old. The prevalence of PCOS phenotypes changed with age. More specifically, the distribution of the phenotypes did not differ substantially between patients ≤20 years old and patients 21–30 years old. However, a decline in the prevalence of phenotype 1 (characterized by anovulation, hyperandrogenemia, and polycystic ovaries) and an increase in the prevalence of phenotype 4 (characterized by anovulation and polycystic ovaries without hyperandrogenemia) were observed in patients 31–39 years old.Conclusion(s): In women with PCOS, hyperandrogenemia appears to diminish during reproductive life whereas insulin resistance worsens.

Effects of acupuncture and exercise on insulin sensitivity, adipose tissue characteristics, and markers of coagulation and fibrinolysis in women with polycystic ovary syndrome: secondary analyses of a randomized controlled trial

2011-12-09

Objective: To investigate the possible effects of low-frequency electroacupuncture (EA) and physical exercise on markers of coagulation and fibrinolysis, insulin sensitivity, and adipose tissue characteristics in women with polycystic ovary syndrome (PCOS).Design: Secondary analyses of a prospective, randomized controlled clinical trial.Setting: Department of Physiology and Department of Obstetrics and Gynecology, University of Gothenburg.Patient(s): Eighty-four women with PCOS were randomized.Intervention(s): Women with PCOS were randomized to 16 weeks of low-frequency EA (14 treatments), physical exercise (at least 3 times/wk), or no intervention.Main Outcome Measure(s): Anthropometrics, circulating coagulation and fibrinolytic markers, insulin sensitivity (euglycemic hyperinsulinemic clamp), hemodynamics, and adipose tissue morphology/function recorded at baseline, after 16 weeks of intervention, and after a 16-week follow-up.Result(s): In the low-frequency EA group, circulating plasminogen activator inhibitor 1 activity decreased by 21.8% after 16 weeks of intervention and by 31.1% at the 16-week follow-up and differed from the physical exercise and the no intervention groups. The EA group had decreases in circulating fibrinogen and tissue plasminogen activator (t-PA), sagittal diameter, and diastolic blood pressure after treatment, and fibrinogen remained lower at the 16-week follow-up. In the physical exercise group, lipoprotein lipase activity increased and diastolic blood pressure decreased after treatment, and both diastolic and systolic blood pressure were lower at follow-up. No other variables were affected.Conclusion(s): Low-frequency EA counteracted a possible prothrombotic state in women with PCOS, as reflected by a decrease in plasminogen activator inhibitor 1 activity. Despite within-group improvements, there were no between-group differences in anthropometric, metabolic, or hemodynamic variables after 16 weeks of EA or physical exercise at the dose/intensity studied.

Androgens and antimüllerian hormone in mothers with polycystic ovary syndrome and their newborns

Eszter Vanky, Sven Magnus Carlsen — 2011-12-12

Objective: To explore the possible effect of metformin on maternal and fetal androgens and antimüllerian hormone (AMH) levels at birth and to study the predictors of maternal and fetal AMH levels.Design: Substudy of a randomized controlled trial (the PregMet study).Setting: University hospital.Patient(s): Women with polycystic ovary syndrome (PCOS) and their newborns (n = 132).Intervention(s): Metformin, 2,000 mg/daily, or placebo from the first trimester until delivery.Main Outcome Measure(s): Androgens and AMH levels in maternal venous serum and in umbilical vein and artery serum.Result(s): Except for the increased free testosterone index (FTI) in the umbilical artery in boys, metformin did not influence maternal or fetal androgens, or AMH levels. The maternal body mass index (BMI) was a negative and FTI a strong positive predictor of maternal AMH levels. Maternal androgens and AMH levels did not correlate to fetal gender. In girls, gestational age, birth weight, or maternal androgens did not correlate to the AMH levels. In boys, birth weight was negatively correlated to the AMH levels.Conclusion(s): Except for FTI, which was higher in boys, metformin had no impact on maternal or fetal androgen levels or the level of AMH. Fetal AMH, as a surrogate marker for ovarian development, was unaffected by maternal androgens. Birth weight and gestational age had no impact on AMH levels in girls; in boys, AMH probably reflects the physiologic variations due to birth weight.Clinical trial registration number: NCT00159536 (www.clinicaltrials.gov).

Erratum

2011-12-12

In the article, “Public perceptions of providing IVF services to cancer and HIV patients” (Fertil Steril 2011; 96: 722–7.e1), the standard deviation of the participants’ age was 16.2 not 2.1. The authors regret the error.

Defining exercise prescription in lifestyle modification programs for overweight/obese polycystic ovary syndrome women

Eduardo Caldas Costa, George Dantas Azevedo — 2011-12-26

We reviewed the manuscript by Nybacka et al. with great interest. The authors randomized overweight/obese women with polycystic ovary syndrome (PCOS) to investigate the effects of different lifestyle modification approaches on ovarian function and endocrine/metabolic parameters. The patients were assigned to diet, exercise, or diet plus exercise for 4 months, and at least 1 year after the termination of the programs they were invited to participate in a follow-up visit. A total of 14, 17, and 12 women completed, respectively, the diet, exercise, and diet plus exercise intervention after 4 months, and seven of each group completed the follow-up visit. At the end of the study, the authors’ conclusion was that “properly managed diet and exercise, alone or in combination, are equally effective in improving reproductive function in overweight/obese women with PCOS, despite the minor weight loss associated with exercise.”

Reply of the Authors

2011-12-26

We were pleased to read the letter by Costa and Azevedo supportive of our findings of individually adapted programs of dietary management and/or physical exercise that are applicable in polycystic ovary syndrome (PCOS). The fact that exercise and diet were equally effective to improve reproductive function independently of weight loss speaks in favor of a common mechanism induced by both diet and exercise. Our preliminary data support the underlying mechanism being involved in enhanced insulin sensitivity. In an extension of our study, we are investigating this further.

Editorial Board

2012-02-01

Fertility and Sterility

Testing the water before swimming: satisfying the need for clinical trials of devices, media, and instruments before their use in assisted reproduction laboratories

Contemporary aspects of male gamete (dys)function: aiming towards optimizing the treatment of fertilization disorders

Development and current applications of assisted fertilization

Semen analysis: looking for an upgrade in class

Epigenetics of the male gamete

Human spermatozoal RNAs

Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome

Genome-wide sperm deoxyribonucleic acid methylation is altered in some men with abnormal chromatin packaging or poor in vitro fertilization embryogenesis

Superoxide dismutase content in sperm correlates with motility recovery after thawing of cryopreserved human spermatozoa

The utility and cost of Chlamydia trachomatis and Neisseria gonorrhoeae screening of a male infertility population

The management of retrograde ejaculation: a systematic review and update

Normal live birth after testicular sperm extraction and intracytoplasmic sperm injection in variant primary ciliary dyskinesia with completely immotile sperm and structurally abnormal sperm tails

Presence of spermatogonia in 47,XXY men with no spermatozoa recovered after testicular sperm extraction

Elective single embryo transfer and perinatal outcomes: a systematic review and meta-analysis

Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging

Developmental potential of embryos from intracytoplasmic sperm injection cycles containing fragmented oocytes

Vaginal (Crinone 8%) gel vs. intramuscular progesterone in oil for luteal phase support in in vitro fertilization: a large prospective trial

Effect of maternal height and weight on risk of preterm birth in singleton and twin births resulting from in vitro fertilization: a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System

A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss

Antitrophoblast antibodies are associated with recurrent miscarriages

Deep infiltrating endometriosis is a determinant factor of cumulative pregnancy rate after intracytoplasmic sperm injection/in vitro fertilization cycles in patients with endometriomas

Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations

Female cancer survivors are low responders and have reduced success compared with other patients undergoing assisted reproductive technologies

Live birth after ovarian tissue autotransplantation following overnight transportation before cryopreservation

Variants of the WNT7A gene in Chinese patients with müllerian duct abnormalities

Origins and rates of aneuploidy in human blastomeres

Should TSPYL1 mutation screening be included in routine diagnostics of male idiopathic infertility?

Knowledge and attitudes regarding expanded genetic carrier screening among women’s healthcare providers

Sex-related differences in association of oxidative stress status with coronary artery disease

Childless women’s knowledge of fertility and assisted human reproduction: identifying the gaps

Informing egg donors of the potential for embryonic research: a survey of consent forms from U.S. in vitro fertilization clinics

Male fertility: psychiatric considerations

Impact of infertility regimens on breast cancer cells: follicle-stimulating hormone and luteinizing hormone lack a direct effect on breast cell proliferation in vitro

Immunization of male mice with B-cell epitopes in transmembrane domains of CatSper1 inhibits fertility

Fertilization outcome could be regulated by binding of oviductal plasminogen to oocytes and by releasing of plasminogen activators during interplay between gametes

Arteriolar insulin resistance in a rat model of polycystic ovary syndrome

Androstenedione induces abnormalities in morphology and function of developing oocytes, which impairs oocyte meiotic competence

Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic stromal cells in spheroid culture

Estriol administration modulates luteinizing hormone secretion in women with functional hypothalamic amenorrhea

Effects of transdermal testosterone on natriuretic peptide levels in women: a randomized placebo-controlled pilot study

Cross-sectional analysis of the effects of age on the hormonal, metabolic, and ultrasonographic features and the prevalence of the different phenotypes of polycystic ovary syndrome

Effects of acupuncture and exercise on insulin sensitivity, adipose tissue characteristics, and markers of coagulation and fibrinolysis in women with polycystic ovary syndrome: secondary analyses of a randomized controlled trial

Androgens and antimüllerian hormone in mothers with polycystic ovary syndrome and their newborns

Erratum

Defining exercise prescription in lifestyle modification programs for overweight/obese polycystic ovary syndrome women

Reply of the Authors

Editorial Board

Table of Contents