Fertility After Endometrial Intraepithelial Neoplasia and Early Endometrial Cancer: Ovulation Induction May Shorten Time to Conception.

The purpose of this study was to determine whether utilization of assisted reproductive technology following clearance of endometrial intraepithelial neoplasia (EIN) or early endometrial cancer (EC) shortens time to conception (TTC) and reduces recurrence. Patients aged 18 to 45 with EIN or early EC who achieved pathologic response following progesterone treatment were identified via retrospective chart review. Study groups included patients who pursued ovulation induction (OI), in vitro fertilization (IVF), and spontaneous pregnancy. Primary outcomes were TTC and recurrence rate. Three hundred forty-six charts were reviewed, with 86 patients meeting inclusion criteria and 53 attempting pregnancy. Of those 53 patients, 11 became pregnant and seven had a live birth. Median times to pregnancy were 183 days for IVF, 54 days for OI, and 347 days for spontaneous conception (p < 0.05). No differences were seen in recurrence or progression based on attempted pregnancy method, nor with duration of fertility treatment. Forty-two of 86 patients (49%) were lost to follow-up. For patients with a history of treated EIN or EC, OI may decrease TTC. Larger prospective studies are needed to definitively answer this question. Although no differences in recurrence or progression were identified, the significant loss to follow-up rate in this study is concerning and warrants further investigation.

Delayed diagnosis of a non-communicating right uterine horn: A case report and literature review.

Background: Accurate diagnosis of a müllerian anomaly is essential for appropriate management and prevention of complications. However, diagnosis is often missed or delayed. Case: This is a case of a nulliparous woman with a müllerian anomaly diagnosed at the age of 36 despite prior evaluation with ultrasound and laparoscopy. Magnetic resonance imaging (MRI) suggested a unicornuate uterus with a right non-communicating rudimentary horn. Hysteroscopy and chromopertubation confirmed the diagnosis. The rudimentary horn was resected laparoscopically using bipolar energy. Conclusion: An undiagnosed müllerian anomaly should be considered in the setting of persistent dysmenorrhea. Three-dimensional ultrasound or MRI should be used judiciously in patients with refractory dysmenorrhea or when ultrasound raises concern for a müllerian anomaly.

The double corpus luteum: A novel sonographic sign of heterotopic pregnancy.

Heterotopic pregnancy is a rare and highly morbid condition with simultaneous intrauterine and extra-uterine pregnancies. The early diagnosis of heterotopic pregnancy is difficult, owing to rarity of the condition and nonspecific clinical and laboratory findings. This case report introduces the "double corpus luteum" sign, a new sonographic and magnetic resonance imaging sign which is easily detectable and should raise the index of suspicion for heterotopic pregnancy. We present a surgically confirmed spontaneous heterotopic and angular pregnancy in a young woman without risk factors or assisted reproductive therapy to illustrate the utility of this novel sign.

Assisted Reproductive Technology and the Reproductive Endocrinology and Infertility Specialist in the U.S. Military.

The U.S. military mirrors the U.S. population given the diverse ethnic and cultural backgrounds of the service members. Active-duty military members, veterans, and Department of Defense beneficiaries can be negatively impacted by infertility.

Does the Presence of Blood in the Catheter or the Degree of Difficulty of Embryo Transfer Affect Live Birth?

The technique used for embryo transfer (ET) can affect implantation. Prior research that evaluated the effect of postprocedural blood of the transfer catheter tip have yielded mixed results, and it is unclear whether this is actually a marker of difficulty of the transfer. Our objective was to estimate the effect of blood at the time of ET and the difficulty of ET on live birth rates (LBR). This retrospective cohort study utilized generalized estimating equations (GEEs) with nesting for repeated cycles for all analyses. Univariate modeling was performed and a final multivariate (adjusted) GEE model accounted for all significant confounders. Embryo transfers were subjectively graded (easy, medium, or hard) by a physician at the time of transfer. The presence of blood at ET was associated with more difficult ETs, retained embryos, and presence of mucous in the catheter. In the univariate analysis, ET with blood was not associated with live birth, while the degree of difficulty for ET had a negative impact on LBR. In the final multivariate GEE model, which accounts for repeated cycles from a patient, the only factors associated with an increased LBR were the degree of difficulty of the ET, female age, and blastocyst transfer. After controlling for confounding variables, the presence of blood in the transfer catheter was not associated with the likelihood of pregnancy and thus was not an independent predictor of cycle outcome. This indicates that the difficulty of the transfer itself was a strong negative predictor of pregnancy.

Seminal vesicle sperm aspiration from wounded warriors.

OBJECTIVE: To assess whether seminal vesicle sperm aspiration (SVSA) is an option for wounded warriors with severe genital and testicular injuries, with the goal of cryopreservation to use in future assisted reproductive technology (ART) cycles. DESIGN: Retrospective case series. SETTING: Tertiary care military hospital. PATIENT(S): Six wounded warriors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Seminal vesicle fluid analysis after harvest, after thaw analysis, fertilization rates, pregnancy rates (PRs), live birth. RESULT(S): Six patients with lower extremity, pelvic, and genital injuries from dismounted improvised explosive devices underwent SVSA within 5-12 days of the initial injury. Sperm retrieved were analyzed (volume, 0.4-1.8 mL; concentration, 40-2,200 K; motility, 0-5%), washed, and cryopreserved. Two patients underwent IVF/intracytoplasmic sperm injection (ICSI) cycles using their samples. In one couple, fertilization rate was 38%. One grade V embryo was transferred with a negative pregnancy test. The second couple underwent two cycles. In their first cycle, fertilization rate was 44%, with one blastocyst transferred and a negative pregnancy test. In the second cycle, fertilization rate was 47%. Two blastocysts were cryopreserved due to ovarian hyperstimulation syndrome (OHSS) concerns. One blastocyst was later transferred in a frozen cycle resulting in a live birth. CONCLUSION(S): The SVSA is a reasonable option to retrieve sperm in wounded warriors or trauma patients with extensive genital injuries.

Intrauterine adhesion prevention after hysteroscopy: a systematic review and meta-analysis.

BACKGROUND: Despite years of studies evaluating prevention strategies for intrauterine adhesion formation after operative hysteroscopy, it is still unclear which strategies are most effective. OBJECTIVE: The objective of the study was to perform a systematic review and meta-analysis to evaluate the effectiveness of postoperative prevention strategies on intrauterine adhesion formation following operative hysteroscopy. STUDY DESIGN: Literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases. Inclusion criteria were published randomized controlled clinical trials from 1989 to 2014 comparing any postoperative preventative measures of intrauterine adhesion after hysteroscopy. The main outcome measure was a reduction in postoperative intrauterine adhesion. Heterogeneity of the studies was evaluated using a Q test and an I(2) index. Analyses were performed using a random-effects model with outcome data reported as relative risk with 95% confidence interval. RESULTS: Twelve studies were included in the systematic review. Eight studies compared similar treatment methods and were included in the meta-analysis. Three studies evaluated hyaluronic acid gel, of which 2 reported a significant decrease in intrauterine adhesion with treatment. The meta-analysis demonstrated a significant reduction of intrauterine adhesion when using hyaluronic acid gel. Two studies evaluated polyethylene oxide-sodium carboxymethylcellulose gel, 1 of which demonstrated a decrease in intrauterine adhesion with treatment. A meta-analysis showed a significant reduction of intrauterine adhesion with polyethylene oxide-sodium carboxymethyl cellulose gel. However, these 3 studies demonstrating a benefit of the gels in preventing adhesion formation were all conducted by the same research group. Other research groups have not confirmed these results. A sensitivity analysis excluding these trials from this single group demonstrated no benefit to adhesion prevention with either gel formation. Three studies investigated oral estrogen therapy after hysteroscopy and found no difference in intrauterine adhesion. A meta-analysis showed no decrease in intrauterine adhesion with estrogen therapy after hysteroscopy. Data were lacking to perform metaanalyses on the use of intrauterine balloon, intrauterine device, and other adhesion prevention barriers in preventing intrauterine adhesion. CONCLUSION: There was a lack of definitive evidence to conclude that any treatment is effective in preventing posthysteroscopy uterine adhesion formation. The available literature has significant heterogeneity and a high risk of bias, making any definitive conclusions difficult.

Are intracytoplasmic sperm injection and high serum estradiol compounding risk factors for adverse obstetric outcomes in assisted reproductive technology?

OBJECTIVE: To evaluate whether intracytoplasmic sperm injection (ICSI) use and E2 on the final day of assisted reproductive technology (ART) stimulation are associated with adverse obstetric complications related to placentation. DESIGN: Retrospective cohort study. SETTING: Large private ART practice. PATIENT(S): A total of 383 women who underwent ART resulting in a singleton live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adverse placental outcomes composed of placenta accreta, placental abruption, placenta previa, intrauterine growth restriction, preeclampsia, gestational hypertension, and small for gestational age infants. RESULT(S): Patients with adverse placental outcomes had higher peak serum E2 levels and were three times more likely to have used ICSI. Adverse placental outcomes were associated with increasing E2 (odds ratio 1.36, 95% confidence interval 1.13-1.65) and ICSI (odds ratio 3.86, 95% confidence interval 1.61-9.27). Adverse outcomes increased when E2 was >3,000 pg/mL and continued to increase in a linear fashion until E2 was >5,000 pg/mL. The association of ICSI with adverse outcomes was independent of male factor infertility. Interaction testing suggested the adverse effect of E2 was primarily seen in ICSI cycles, but not in conventional IVF cycles. Estradiol >5,000 pg/mL was associated with adverse placental events in 36% of all ART cycles and 52% of ICSI cycles. CONCLUSION(S): ICSI and elevated E2 on the day of hCG trigger were associated with adverse obstetric outcomes related to placentation. The finding of a potential interaction of E2 and ICSI with adverse placental events is novel and warrants further investigation.

Impact of a prior cesarean delivery on embryo transfer: a prospective study.

OBJECTIVE: To determine whether a history of prior cesarean delivery (CD) makes ET more difficult and impacts pregnancy outcomes. DESIGN: Prospective cohort study. SETTING: Tertiary care military facility. PATIENT(S): One hundred ninety-four patients with previous delivery undergoing IVF/intracytoplasmic sperm injection (ICSI)-ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth (primary), positive hCG, clinical pregnancy, and time to perform ET. RESULT(S): There was no statistically significant difference between patients with a history of only vaginal deliveries versus those with a history of CD for live birth (39% vs. 32%), positive hCG (56% vs. 53%), or clinical pregnancy (49% vs. 41%). Embryo transfers took longer in the history of CD group (157 vs. 187 seconds) and were more likely to have mucus (27% vs. 45%) or blood (8% vs. 21%) on the catheter. CONCLUSION(S): Embryo transfers performed on patients with a prior CD took 30 seconds longer. They were also more likely to have blood or mucus on the catheter. Despite the apparently more difficult transfers, pregnancy outcomes were not different between the two groups.

Human sperm bind to the N-terminal domain of ZP2 in humanized zonae pellucidae in transgenic mice.

Fertilization requires taxon-specific gamete recognition, and human sperm do not bind to zonae pellucidae (ZP1-3) surrounding mouse eggs. Using transgenesis to replace endogenous mouse proteins with human homologues, gain-of-function sperm-binding assays were established to evaluate human gamete recognition. Human sperm bound only to zonae pellucidae containing human ZP2, either alone or coexpressed with other human zona proteins. Binding to the humanized matrix was a dominant effect that resulted in human sperm penetration of the zona pellucida and accumulation in the perivitelline space, where they were unable to fuse with mouse eggs. Using recombinant peptides, the site of gamete recognition was located to a defined domain in the N terminus of ZP2. These results provide experimental evidence for the role of ZP2 in mediating sperm binding to the zona pellucida and support a model in which human sperm-egg recognition is dependent on an N-terminal domain of ZP2, which is degraded after fertilization to provide a definitive block to polyspermy.

Proficiency in oocyte retrieval: how many procedures are necessary for training?

OBJECTIVE: To determine a minimum number of procedures required for proficiency in oocyte retrieval and to characterize skill acquisition. DESIGN: Retrospective analysis. SETTING: Reproductive endocrinology and infertility fellowship training program. SUBJECT(S): Fellows in training from 2005 to 2007 and 2008 to 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proficiency scores were calculated by dividing the number of oocytes retrieved by oocytes expected. The 2005 to 2007 trainees were grouped and proficiency scores calculated as an average during specific points in their training. The 2008 to 2010 trainees were compared individually to determine differences in individual skill acquisition. RESULT(S): A greater number of oocytes were retrieved than expected, 8.6 versus 7.6. A relatively lower proficiency score was noted during the first 10 trainee aspirations (proficiency score=1.1) compared with subsequent aspirations (proficiency score=1.25 for retrievals 11-20, proficiency score=1.21 for retrievals 21-30 and >31). When individual fellows' scores were calculated, the majority achieved proficiency by 20 aspirations, and all but one trainee achieved the mean staff proficiency score by 50 retrievals. CONCLUSION(S): Regardless of a trainee's initial proficiency in oocyte retrieval, there were no statistically significant differences in the learning curve between trainees. The majority of individual fellows in training demonstrate proficiency in follicular aspirations within 20 procedures; however, a minority may require 50 procedures to achieve the proficiency of an attending physician.

Human ZP4 is not sufficient for taxon-specific sperm recognition of the zona pellucida in transgenic mice.

The molecular basis of human fertilization remains enigmatic. Mouse models are often used to study sperm-egg recognition, but the mouse zona pellucida surrounding ovulated eggs contains three proteins (ZP1, ZP2, and ZP3) whereas the human zona contains four (ZP1, ZP2, ZP3, and ZP4). Human sperm are fastidious and recognize human but not mouse eggs. Transgenic mouse lines were established to ascertain whether human ZP4 is the sole determinant of human sperm binding. Human ZP4 expressed in transgenic mice had a molecular mass similar to the range of native protein isoforms and was incorporated into the extracellular zona matrix. Transgenic females were fertile with normal litter sizes. Mouse sperm readily recognized transgenic ovulated eggs, but human sperm did not. We conclude that human ZP4 is not sufficient to support human sperm binding to the zona pellucida in transgenic mice and that other zona proteins may be needed for human gamete recognition.

Cost analysis model of outpatient management of ovarian hyperstimulation syndrome with paracentesis: "tap early and often" versus hospitalization.

OBJECTIVE: To compare the cost of two treatment regimens for moderate to severe ovarian hyperstimulation syndrome (OHSS): conservative inpatient versus outpatient management with paracentesis. DESIGN: A decision-tree mathematical model comparing conservative inpatient versus outpatient management of moderate to severe OHSS was created. The common final pathway of either management was resolution of OHSS. Sensitivity analyses were performed over the range of variables. MAIN OUTCOME MEASURE(S): Total management cost of OHSS. RESULT(S): The cost of conservative therapy including first-tier complications was $10,099 (range $9,655-$15,044). The cost of outpatient management with paracentesis was $1954 (range $788-$12,041). This resulted in an estimated cost savings of $8145 with outpatient management with paracentesis. One-way sensitivity analyses were performed. Varying the probability of admission after outpatient treatment still indicated that outpatient treatment was the most cost-effective (probability = 1.0, cost = $6110). Varying the duration of hospitalization with primary inpatient treatment was equal to outpatient treatment costs only at a stay of 0.71 days or shorter. CONCLUSION(S): Our model suggests early outpatient paracentesis for moderate to severe OHSS is the most cost-effective management plan when compared with traditional conservative inpatient therapy. The cost savings for outpatient management persisted throughout a variety of outcome probabilities.

Balloon fluoroscopy as treatment for intrauterine adhesions: a novel approach.

OBJECTIVE: To report a unique fluoroscopically guided approach to treat severe intrauterine adhesions and cervical stenosis using balloon hysteroplasty. DESIGN: Case report. SETTING: Military-based fertility center. PATIENT(S): A 33-year-old woman undergoing assisted reproductive technology whose uterus could not be cannulated because of the development of intrauterine synechiae and cervical stenosis after a post-IUI infection that was further complicated by a prominent lower uterine segment-filling defect in the location of a prior cesarean delivery scar. INTERVENTION(S): Fluoroscopic cannulation and balloon uterine dilation. MAIN OUTCOME MEASURE(S): Resolution of synechiae by hysterosalpingogram and successful uterine cannulation. RESULT(S): A postprocedure hysterosalpingogram demonstrated a normalized uterine cavity with the exception of a persistent prominent lower uterine segment-filling defect from a prior cesarean delivery. A frozen ET cycle was performed successfully. CONCLUSION(S): Hysteroplasty, using standard interventional radiographic techniques, may provide an alternative treatment modality for patients with intrauterine adhesions and lower uterine defects from prior cesarean deliveries in select cases. While treating intrauterine adhesions improves pregnancy outcome, the effect of lower uterine segment-filling defects from cesarean deliveries on pregnancy outcome in assisted reproductive technology cycles warrants further investigation.

Effect of depot medroxyprogesterone acetate on glucose tolerance in generalized lipodystrophy.

BACKGROUND: Lipodystrophy is a rare condition causing severe insulin resistance and frank diabetes. Depot medroxyprogesterone acetate (DMPA), a commonly used contraceptive, may worsen glucose tolerance in diabetics and those with lipodystrophy. CASE: A young woman with generalized lipodystrophy, who previously required greater than 1,000 units of insulin daily, had a normal hemoglobin A1c on leptin and metformin only. After an injection of DMPA, she developed severe hyperglycemia. Her levels returned to near normal only with extremely high doses of insulin (up to 1,700 units/d) and increased doses of leptin and metformin. CONCLUSION: Progestin-only contraceptives may detrimentally affect glucose tolerance, particularly in patients with lipodystrophy, a cause of severe insulin resistance and leptin deficiency. One DMPA injection appeared to profoundly alter glucose metabolism in this patient with frank diabetes resulting from lipodystrophy. The effect of progestin-only contraceptives on glucose tolerance should be monitored closely in any diabetic patient.

Blastocyst development rate impacts outcome in cryopreserved blastocyst transfer cycles.

OBJECTIVE: To assess cycle outcome among day 5 and day 6 cryopreserved frozen-thawed blastocyst embryo transfers (FBET). DESIGN: Retrospective cohort study. SETTING: Military-based assisted reproduction technology (ART) center. PATIENT(S): One hundred seventy-two nondonor, programmed cryopreserved embryo cycles. INTERVENTION(S): Fully expanded blastocysts on day 5 were cryopreserved on day 5, and those achieving this state on day 6 were cryopreserved on day 6. Leuprolide acetate was given for ovulation inhibition, and endometrial supplementation was by oral and vaginal estradiol. Progesterone in oil was administered, and blastocyst transfer occurred in the morning of the sixth day of progesterone. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and live-birth rates. RESULT(S): Fresh and frozen cycle characteristics were similar between groups. Day-5 FBET had statistically significantly higher implantation rates (32.2% vs. 19.2%), which remained significant even when adjusting for covariates (odds ratio: 1.91; 95% confidence interval, 1.00, 3.67). Live-birth rates trended toward improvement after adjusting for covariates (odds ratio: 1.18; 95% confidence interval, 0.61, 2.30). CONCLUSION(S): Cryopreserved day-5 blastocysts have higher implantation rates and trend toward improved pregnancy outcomes compared with cryopreserved day-6 blastocysts. This suggests that embryo development rate may, in part, predict implantation and subsequent FBET outcomes, although embryos not achieving the blastocyst stage until day 6 still demonstrate acceptable outcomes.

Pre-cycle saline infusion sonography minimizes assisted reproductive technologies cycle cancellation due to endometrial polyps.

Pre-ART cycle screening with saline infusion sonohysterography is effective at limiting cycle cancellation caused by endometrial polyps to 0.5%. Although a thickened lining at the time of baseline ultrasound can be indicative of a uterine polyp, a normal endometrial lining does not eliminate the possibility that a polyp will be discovered during the cycle.

Default from colposcopy and loop excision electrocautery procedure appointments in a military clinic.

OBJECTIVE: To determine the extent of nonadherence and impediments to care in a military colposcopy and loop excision electrocautery procedure (LEEP) clinic. MATERIALS AND METHODS: The nonadherence rate for colposcopy and LEEP appointments was determined for a 6-month period at Walter Reed Army Medical Center. Nonadherence was defined as failure to keep an appointment or cancellation within 24 hours of the scheduled time. A nurse coordinator telephoned all nonadherent women. Women who agreed to participate were administered a structured survey to elicit their reasons for default from their appointments. RESULT: Sixty-one (15%) of 405 women were nonadherent. Of the 61 nonadherent women, 55 (90%) agreed to participate, 4 (7%) were unable to be contacted, and 2 (3%) declined participation. The average age of participants was 30 years. Beneficiary status of the 55 women was as follows: dependent, 27 (49%); active duty, 25 (45%); retired, 2 (4%); and veteran, 1 (2%). The most common reasons for default overall for 55 women were onset of menses (15 [27%]), unplanned family or personal event (9 [16%]), forgetting (8 [15%]), and work conflict (7 [13%]). Leading reasons for 25 active duty women included work conflict (7 [28%]) and menses (6 [24%]). Leading reasons for 27 dependent women included menses (9 [33%]), unplanned family or personal event (6 [22%]), and forgetting (5 [19%]). CONCLUSIONS: Despite unrestricted access to care in the military clinic, the default rate was similar to rates reported for civilian clinics. Previsit interventions likely to improve compliance include sending informational packets to patients, better attention to scheduling around the time of expected menses, and initiating an appointment reminder system. To decrease the high percentage of nonadherence attributable to work conflicts for active duty women, supervisors need to be better informed about both medical and deployment implications of an unevaluated abnormal Pap smear.