In vitro fertilization outcomes after preimplantation genetic testing for chromosomal structural rearrangements comparing fluorescence in-situ hybridization, microarray comparative genomic hybridization, and next-generation sequencing.

OBJECTIVE: To compare in vitro fertilization (IVF) outcomes for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) using various testing platforms. DESIGN: Retrospective cohort. SETTING: Large academic IVF center. PATIENTS: Fifty-one balanced translocation carriers undergoing IVF with PGT-SR who completed a total of 91 cycles, including 31 fluorescence in-situ hybridization (FISH), 24 microarray comparative genomic hybridization (aCGH), and 36 next-generation sequencing (NGS) testing cycles. INTERVENTIONS: PGT-SR. MAIN OUTCOME MEASURES: Primary outcome of live-birth rate and secondary outcomes including implantation rate, clinical loss rate, and percentages of normal or balanced, unbalanced, and aneuploid embryos detected. RESULTS: There was no statistically significant difference in LBR, though there was a tendency toward a higher LBR for NGS testing (14 of 19, 73.7%) compared with FISH (8 of 18, 44.4%) and aCGH (10 of 20, 50.0%). The implantation rate was statistically significantly higher for NGS (16 of 20, 80.0%) compared with FISH (11 of 25, 44.0%) and aCGH (16 of 30, 53.3%). There was no statistically significant difference in clinical pregnancy losses. There was a lower percentage of normal or balanced embryos with FISH (12.5%) compared with aCGH (23.7%) and with NGS (20.7%). CONCLUSIONS: This is the first report of PGT-SR outcomes for translocation carriers directly comparing PGT-SR using FISH, aCGH, and NGS. Our findings suggest an improvement in pregnancy outcomes parallel to the advancement in technology and are reassuring for continued use of NGS for this population.

The window is wide: flexible timing for vitrified-warmed embryo transfer in natural cycles.

RESEARCH QUESTION: What is the optimal timing for transfer in natural cycle vitrified-warmed embryo transfers (NC-VET)? DESIGN: This retrospective cohort study uses data from a large university-affiliated IVF clinic. The study included 341 NC-VET cycles with autologous oocytes and non-preimplantation genetic testing, vitrified embryos from January 2013 to September 2017. Each cycle was classified by timing of embryo transfer in relation to LH surge ≥20 IU/l. Group 1: LH ≥20 IU/l one day and blastocyst was transferred 6 days later; Group 2: LH ≥20 IU/l two consecutive days and blastocyst was transferred 6 days after the initial surge; Group 3: LH ≥20 IU/l two consecutive days and blastocyst was transferred 7 days after the initial surge. The primary outcome was ongoing pregnancy rate (OPR). The secondary objective was to compare OPR in relation to serum oestradiol dynamics and progesterone concentration (according to threshold 1.0 ng/ml) 6 days prior to embryo transfer. RESULTS: OPR were similar for all three groups (66.8%, 65.0%, 62.9% for Groups 1, 2 and 3, respectively). When stratified according to oestradiol and progesterone, no significant differences were noted in OPR. CONCLUSIONS: The results suggest that the timing of blastocyst transfer in a natural cycle after LH surge is flexible within 24 h. Outcomes are equally good with day of embryo transfer 6 or 7 days after LH surge date. Oestradiol dynamics and progesterone concentration 6 days prior to NC-VET did not have a significant impact on OPR.

Second try: who returns for additional assisted reproductive technology treatment and the effect of a prior assisted reproductive technology birth.

OBJECTIVE: To evaluate the effect of a prior assisted reproductive technology (ART) live birth on subsequent live-birth rates. DESIGN: Historical cohort study. SETTING: Clinic-based data. PATIENT(S): The study population included 297,635 women with 549,278 cycles from 2004 to 2010 from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. Try 1 refers to ART cycles up to and including the first live birth, try 2 to ART cycles after a first live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rates by cycle number, try number, and oocyte source. RESULT(S): Younger women at try 1 are more likely to return for try 2. Women returning for try 2 were more likely to have had an ART singleton versus multiple birth (33.2% after a try 1 singleton versus 8.1% after twins and 4.9% after triplets) and were less likely to have a diagnosis of diminished ovarian reserve or tubal factors. Live-birth rates were significantly higher for try 2 compared with try 1 for autologous fresh cycles, averaging 7.7 percentage points higher over five cycles. Live-birth rates were not significantly different for try 2 versus try 1 with thawed autologous cycles or either fresh or thawed donor cycles. CONCLUSION(S): These results indicate that when fresh autologous oocytes can be used, live-birth rates per cycle are significantly greater after a prior history of an ART live birth.

Antral follicle count in clinical practice: analyzing clinical relevance.

OBJECTIVE: To determine the clinical relevance of obtaining antral follicle counts (AFC) before ovarian stimulation in an IVF program. DESIGN: Retrospective cohort study. SETTING: An IVF program in a large academic teaching hospital. PATIENT(S): A total of 1,049 stimulated IVF cycles in 734 subjects between September 2003 and December 2007 selected from our program's database. INTERVENTION(S): Basal antral follicles (AFCs) (3 mm-10 mm) were counted via ultrasound scan on cycle day 3 in luteal leuprolide acetate stimulations, or after at least 2 weeks of oral contraceptives in microdose leuprolide acetate stimulations. Patients were grouped according to basal AFC, and outcome parameters compared for AFC groups within each stimulation protocol. MAIN OUTCOME MEASURE(S): Oocytes retrieved, ovarian response, implantation rate, cancellations, pregnancy, pregnancy loss, and live births per cycle start. RESULT(S): Antral follicle count grouping is predictive of threefold change in ovarian response to gonadotropins and oocytes retrieved. Low AFC did predict a higher cancellation rate. Antral follicle count did not predict implantation rate, pregnancy rate, or live birth rate per cycle start. CONCLUSION(S): Antral follicle count may be helpful in determining stimulation protocol, as it is the most reliable determinant of oocytes retrieved per starting FSH dose. Antral follicle count predicts ovarian response, not embryo quality or pregnancy.

Testosterone may increase selective attention to threat in young male macaques.

Animal studies indicate that sex hormones have widespread effects on the brain, cognition and emotion, but findings in humans are inconsistent. Well-controlled studies in nonhuman primates are crucial to resolve these discrepancies. In this study, we examined the effects of testosterone (T) on emotion in male rhesus monkeys. Six young adult males were tested on two emotional tasks during three hormonal conditions in a crossover design: when intact at baseline and when pharmacologically hypogonadal with add-back of T or placebo. The emotional tasks were the Approach-Avoidance task, which tested behavioral responses to three categories of objects (familiar, novel, and negative) and a Social Playback task which tested behavioral responses to scenes of unfamiliar conspecifics engaged in three types of social activities (neutral, positive, or negative). Following a 4-week baseline period, monkeys were treated with Depot Lupron, 200µg/kg before being randomly assigned to one of two treatment groups: Depot Lupron+Testosterone Enanthate (TE, 20mg/kg) or Depot Lupron+oil vehicle. In each treatment group, monkeys received one injection of Lupron and one injection of TE or one injection of Lupron and one injection of oil at the onset of a 4-week testing period, before crossing over to the alternate treatment for an additional 4weeks of testing. TE treatment had no effect on behavioral measures in the Approach-Avoidance task. For the Social Playback task, however, TE significantly increased watching time of video clips which depicted fights between unfamiliar conspecifics. The enhancing effect of T on watching time for negative social scenes is consistent with human data suggesting that T decreases aversion or facilitates approach to threatening social stimuli. Further studies are needed to understand the mechanisms by which T may mediate responsiveness to social threat in male primates.

Effects of testosterone on cognition in young adult male rhesus monkeys.

The relationships between testosterone (T) and cognitive function remain unclear. In men, associations between endogenous T levels and cognitive performance have not consistently been found and the effects of T treatment on cognition remain ambiguous: several studies have reported beneficial effects of T administration on cognitive function, but recent data indicate no effect or even detrimental effects of T. Studies in nonhuman primates may help resolve these discrepancies. We conducted the first study examining the activational effects of T on cognition in adult male nonhuman primates. Six young adult male rhesus monkeys (5-6 years old) were tested for 16 weeks on a battery of 4 memory tasks (1) when intact at baseline (winter); (2) when hypogonadal with add-back of T or placebo in a double blind cross-over design and (3) when intact following wash-out (summer phase). The cognitive tasks consisted of the Delayed Non-Matching-To-Sample (DNMS) with mixed delays, the spatial-Delayed Recognition Span Test (spatial-DRST) and the Delayed Response (DR) task. Following a 4-week baseline period, monkeys were treated with a gonadotropin releasing hormone (GnRH) agonist (Depot Lupron, 200 microg/kg) before being randomly assigned to one of 2 treatment groups: Lupron+testosterone enanthate (TE, 20 mg/kg) or Lupron+oil vehicle. In each treatment group, monkeys received Lupron+TE, or Lupron+oil, for 4 weeks before crossing over to the alternate treatment for an additional 4weeks. After a 2 months wash-out period, monkeys were retested on the battery of tasks for an additional 4weeks. T levels did not vary significantly between the winter and summer months of testing, indicating a lack of seasonal effect in these monkeys housed indoors. TE treatment yielded supraphysiological T levels decreasing progressively over 4 weeks. This treatment was associated with impaired recognition memory at the 600s delay of the DNMS, suggesting compromised medial temporal lobe function, but had no effect on DR or spatial-DRST. Further studies are needed to determine whether T may enhance memory in aged male monkeys.

Gonadotropin-releasing hormone agonist pretreatment did not decrease postoperative adhesion formation after abdominal myomectomy in a randomized control trial.

OBJECTIVE: To determine if 3 months of preoperative gonadotropin-releasing hormone agonist (GnRH-a) treatment decreases postoperative uterine adhesions after open abdominal surgery for the removal of uterine fibroids. DESIGN: Prospective, randomized, clinical study. SETTING: A tertiary care medical center. PATIENT(S): Women of reproductive age with symptomatic uterine fibroids not amenable to hysteroscopic removal. INTERVENTION(S): Twenty patients underwent an initial abdominal myomectomy followed by a second-look laparoscopy for evaluating uterine adhesions after random allocation to groups receiving either GnRH analog or placebo for 3 months before the initial surgery. MAIN OUTCOME MEASURE(S): Adhesion formation between treatment groups and by incision number and aggregate length. RESULT(S): Presurgical GnRH-a treatment did not decrease adhesion formation compared with placebo. For every additional centimeter of incision length, the total adhesion area over the uterine serosal surface increased by 0.55 cm(2). The number of myomas removed and the number of incisions were positively correlated with total adhesion area. CONCLUSION(S): Preoperative treatment with GnRH-a for 3 months before open abdominal myomectomy did not decrease postoperative uterine adhesions. Following the standards of good surgical technique, adhesions are minimized with fewer and smaller incisions.

Virtual reality and computer-enhanced training devices equally improve laparoscopic surgical skill in novices.

BACKGROUND: The study aim was to compare the effectiveness of virtual reality and computer-enhanced videoscopic training devices for training novice surgeons in complex laparoscopic skills. METHODS: Third-year medical students received instruction on laparoscopic intracorporeal suturing and knot tying and then underwent a pretraining assessment of the task using a live porcine model. Students were then randomized to objectives-based training on either the virtual reality (n=8) or computer-enhanced (n=8) training devices for 4 weeks, after which the assessment was repeated. RESULTS: Posttraining performance had improved compared with pretraining performance in both task completion rate (94% versus 18%; P<0.001*) and time [181+/-58 (SD) versus 292+/-24*]. Performance of the 2 groups was comparable before and after training. Of the subjects, 88% thought that haptic cues were important in simulators. Both groups agreed that their respective training systems were effective teaching tools, but computer-enhanced device trainees were more likely to rate their training as representative of reality (P<0.01). CONCLUSIONS: Training on virtual reality and computer-enhanced devices had equivalent effects on skills improvement in novices. Despite the perception that haptic feedback is important in laparoscopic simulation training, its absence in the virtual reality device did not impede acquisition of skill.

Turner mosaicism (45,X/46,XX) diagnosed in a young woman subsequent to low oocyte maturity and failed ICSI.

OBJECTIVE: To report a case of Turner mosaicism with low oocyte maturity during ICSI. DESIGN: Retrospective case report. SETTING: Academic tertiary medical center. PATIENT(S): A 28-year-old patient with 7-year history of primary unexplained infertility. INTERVENTION(S): Four cycles of ICSI. MAIN OUTCOME MEASURE(S): Oocyte quality; fertilization, cleavage, and implantation rates; and live births during ICSI cycles; as well as patient karyotype were obtained. RESULT(S): Over four cycles of ICSI, 111 oocytes were harvested, a high follicular response, but 68% were immature (germinal vesicles or metaphase I). Additionally, seven embryos were transfered, but none implanted. Owing to this unusual response in a young healthy woman, maternal karyotype was performed, which demonstrated 17% Turner mosaicism. CONCLUSION(S): This is, to our knowledge, the first reported case of excellent ovarian response but marked oocyte immaturity in a young woman with Turner mosaicism. The implications of sex chromosome aneuploidy on fertility and the significance of low oocyte maturity are discussed.

Novices outperform experienced laparoscopists on virtual reality laparoscopy simulator.

BACKGROUND AND OBJECTIVES: Virtual reality has been poorly studied among gynecologic surgeons. The aim of this study was to evaluate whether performance on the Minimally Invasive Surgery Trainer-Virtual Reality (MIST-VR) laparoscopic trainer reflects laparoscopic experience among gynecologic surgeons and trainees. METHODS: Twenty-six medical students, residents, and attending gynecologic surgeons completed a MIST-VR training program. A new simulated task was then presented to each participant, who repeated the task until proficiency was reached. RESULTS: Attending physicians performed poorly when compared with medical students, requiring more than twice the number of attempts to reach proficiency (Mann-Whitney P<0.01). Among medical students and residents, there was an association between years of live laparoscopy experience and poor simulator performance (Spearman r P=0.01). CONCLUSION: Increased operating room experience and age were associated with worsening simulator performance. Several potential explanations for this trend are discussed, including lack of tactile and contextual feedback. Caution should be exercised when considering current virtual reality simulator technology as a measure of experience or ability among gynecologic surgeons.

Fertility services for human immunodeficiency virus-positive patients: provider policy, practice, and perspectives.

OBJECTIVE: To examine demand for, and access to, fertility services for HIV-positive patients in the United States. DESIGN: An electronic survey. SETTING: The URL for the Web-based survey was e-mailed to those surveyed. PATIENT(S): The 916 members of the Society of Reproductive Endocrinology and Infertility of the American Society of Reproductive Medicine. MAIN OUTCOME MEASURE(S): Policy and practice in evaluation and treatment of HIV-positive and HIV-serodiscordant couples who desire conception, demand for services, and perceived barriers to providing these services. RESULT(S): The response rate was 22%. Forty percent of respondents reported policies. Fifty-one percent reported requests. Sixty-four percent reported offering treatment to HIV-serodiscordant couples, and 57% reported offering treatment to HIV-positive couples. Treatments most frequently offered to HIV-serodiscordant male-positive couples were reproductive surgery (50%), ovulation induction (46%), and intracytoplasmic sperm injection (45%). Twenty-nine percent of those offering treatment test-washed specimens for HIV. Factors limiting care included the following: low volume of requests (45%), concern for child welfare (37%), no laboratory policy (32%), and legal risk (32%). CONCLUSION(S): Patients who are HIV-positive are seeking fertility services in the United States. The small demand is a major limiting factor to provision of services. There is a lack of global application of current American Society of Reproductive Medicine guidelines. Provider education is needed to ensure that the safest reproductive services are offered to HIV-positive patients. Legal reform is imperative to improve access to reproductive services for the HIV-positive population.

Oral contraceptives maintain a very thin endometrium before operative hysteroscopy.

OBJECTIVE: To show that early follicular-phase administration of an oral contraceptive pill (OC) consistently provides a thin endometrium, as determined by transvaginal ultrasound. This is an ideal condition when performing operative hysteroscopy. DESIGN: Retrospective chart review of patients who have undergone ultrasound evaluation of the endometrial thickness under different hormonal conditions. Endometrial measurement was obtained during menstruation, in the late follicular phase, and in the luteal phase in 20 patients. In another group of 100 patients, endometrial measurement was made on the 18th day of OC administration, initiated during menses. SETTING: A reproductive endocrinology unit in a university-affiliated medical center. PATIENT(S): Patients undergoing treatment for subfertility of various etiologies. INTERVENTION(S): Transvaginal ultrasound measurements of the endometrium. MAIN OUTCOME MEASURE(S): Endometrial thickness by transvaginal ultrasound. RESULT(S): Combination OCs started on menstrual days 1-3 maintain a uniformly thin endometrium, 4.1 +/- 1.6 mm (mean +/- SD), comparable to menstrual endometrium (3.7 +/- 1.5 mm). This was statistically thinner compared with endometrium observed in the late follicular phase (11 +/- 2.0 mm) or late luteal phase (12 +/- 2.3 mm). Transvaginal ultrasound measurements of the endometrium under different conditions were compared by the unpaired t-test. CONCLUSION(S): Oral contraceptives maintain a very thin, flat endometrium, such that lesions might be readily identified and treated during operative hysteroscopy procedures. Prevention of pregnancy and endometrial thinning with administration of OCs facilitates procedural scheduling for patients and surgeons.

Influence of embryo transfer depth on in vitro fertilization and embryo transfer outcomes.

OBJECTIVE: To investigate the influence of transfer distance from the fundus (TDF) on clinical pregnancy rate (PR) and ectopic pregnancy rate. DESIGN: Retrospective cohort. Between January 2000 and December 2001, 699 ultrasound (US)-guided embryo transfers were conducted. Mock transfer was performed to measure uterine cavity depth 1 month before treatment. Cavity depth was measured by abdominal US before the transfer, from the vaginal stripe to the fundus. Transfers were performed with a Wallace embryo transfer catheter (Cooper Surgical, Shelton, CT) using US and physician's judgment of cavity depth. Transfer distance from the fundus was calculated by subtracting the depth of catheter insertion from the cavity depth, as determined by US or by mock transfer. Statistical analyses were performed by building a multivariable logistic regression model to calculate odds ratios and 95% confidence intervals (CI). SETTING: Women aged 23 to 43 years who are in a university-affiliated, community-based IVF program in Springfield, Massachusetts. PATIENT(S): All patients enrolled in IVF program undergoing embryo transfer. INTERVENTION(S): No patient received any additional procedure or intervention. All of the measurements obtained with the embryo catheter and the transvaginal ultrasound were part of the program's protocol for the embryo transfer. MAIN OUTCOME MEASURE(S): Odds ratio examining relationship between embryo transfer depth and PR.Clinical, implantation, and ectopic PR were 37%, 20%, and 2.1%. Cavity depth by US differed from cavity depth by mock by at least 10 mm in >30% of cases. The TDF by US was highly predictive of PR; TDF by mock was not predictive of PR. Increasing the TDF by US resulted in significantly increased PR as well as lower ectopic rates. Using regression analysis, the odds ratio for TDF by US was 1.11 (95% CI: 1.07-1.14). This suggests that for every additional millimeter embryos are deposited away from the fundus, the odds of clinical pregnancy increased by 11%. CONCLUSION(S): After controlling for potential confounders, the clinical PR is significantly influenced by the transfer distance from the fundus. Cavity depth by US is clinically useful to determine the depth beyond which catheter insertion should not occur.

Metabolism of endogenous and exogenous reproductive hormones.

Estradiol and progesterone are produced in abundance by the ovary of the reproductive-age female (and by the placenta in pregnancy). Serum levels of both hormones are very low in the postmenopause, and indistinguishable from women who have undergone castration. Postmenopausal women have higher levels of aromatase in skin and adipose and convert androstenedione to estrone more effectively than younger women. Estradiol is well absorbed orally, but undergoes extensive first-pass effect resulting in production of the less potent metabolites estrone and estrone sulfate. Ethinyl estradiol is well absorbed, potent, and has more pronounced effects in the production of important hepatic proteins. Progesterone is absorbed orally only if ingested in a micronized form, has a relatively short serum half-life, and is metabolized to products with little biologic activity. The synthetic progestogens are abundant in number; potent in effect; and well absorbed orally, vaginally, and transdermally. New formulations of estrogens and progestogens and new delivery systems promise to provide gynecologists and patients with a long list of potential solutions to contraceptive needs and alternatives for hormone replacement therapies.

Does catheter type effect pregnancy rate in intrauterine insemination cycles?

PURPOSE: To determine if a soft insemination catheter increases pregnancy rates. METHODS: Seven hundred forty-seven consecutive intrauterine insemination (IUI) cycles in 364 women in a reproductive endocrinology office between October 1998 and March 2000. Patients with even birth years were inseminated with the Tomcat catheter, and those with odd birth year with the Wallace IUI catheter. Clinical pregnancy rates were compared. RESULTS: The Wallace catheter group included 180 women for 372 cycles and an overall pregnancy rate of 16.4%. The Tomcat catheter group included 184 women for 375 cycles and an overall pregnancy rate of 18.1%. This difference is not statistically significant (P = 0.61). Potential confounders were accounted for. CONCLUSIONS: When comparing the softer Wallace catheter to the less pliable Tomcat catheter during IUI cycles, there was no significant difference in pregnancy rate when using a standard gentle technique that includes not touching the top of the fundus with the catheter.