Planned oocyte cryopreservation in women with blepharophimosis-ptosis-epicanthus inversus syndrome: a case series.

OBJECTIVE: To describe the experiences of three women with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) who desired to pursue planned oocyte cryopreservation. DESIGN: Case series. SETTING: An academic institution and a private clinic. PATIENTS: Three nulligravid women aged 23, 25, and 34 years who desired to pursue planned oocyte cryopreservation. Two women had BPES diagnosed when they were infants and one had BPES diagnosed after presenting to discuss oocyte cryopreservation. INTERVENTIONS: All three women underwent ovarian stimulation. One woman underwent three oocyte retrievals. MAIN OUTCOMES MEASURES: Vitrification of metaphase II oocytes. RESULTS: One woman had a total of eight metaphase II oocytes vitrified. In addition, she underwent genetic testing that confirmed type 1 BPES. The other two women, who had BPES diagnosed when they were newborns, each underwent two cycles of ovarian stimulation. Neither of these two women responded to ovarian stimulation and both cycles were cancelled before oocyte retrieval. CONCLUSIONS: BPES is a rare condition that can lead to primary ovarian insufficiency. Early identification of this condition is important to allow for timely reproductive counseling so that oocyte cryopreservation can be offered at a young age before oocyte depletion. Careful counseling is critical for these patients, because this case series demonstrated that not all women with BPES will respond to stimulation. Further, outcomes with cryopreserved oocytes have not yet been described in women with BPES.

High incidence of diminished ovarian reserve in young unexplained recurrent pregnancy loss patients.

Recurrent pregnancy loss (RPL) is a clinically challenging scenario for patients and providers since an evidence-based approach to evaluation results in no explanation at least 50% of the time. The most common cause of first trimester clinical miscarriage is chromosome imbalance in the embryo or aneuploidy and the incidence of aneuploidy increases with age and diminished ovarian reserve (DOR). Currently, no professional societies recommend ovarian reserve testing in RPL patients, but some research shows a higher rate of DOR in miscarriage patients. The objective of this study was to evaluate the prevalence of DOR in unexplained vs. explained RPL patients. A prospective cohort study was completed, including 264 patients with recurrent pregnancy loss, 87 with an identifiable cause and 177 patients unexplained. A higher percentage of patients with unexplained RPL had DOR compared to patients with a known cause for RPL (48% vs 29%, p = .005). This finding was most significant in patients less than 38 years old compared to patients 38 years old and older (22% vs. 12%, p = .04). In conclusion, DOR is associated with RPL in many patients with otherwise unexplained RPL. Providers should consider adding ovarian reserve testing to their evaluation of RPL patients to guide counseling for treatment options.

Higher rates of aneuploidy in blastocysts and higher risk of no embryo transfer in recurrent pregnancy loss patients with diminished ovarian reserve undergoing in vitro fertilization.

OBJECTIVE: To study the prediction of aneuploidy rate in blastocysts from patients with recurrent pregnancy loss (RPL) on the basis of ovarian reserve testing. DESIGN: Prospective cohort analysis. SETTING: Private, university-affiliated fertility clinic. PATIENT(S): A total of 239 patients with RPL, defined as two or more clinical miscarriages, were screened for inclusion. One hundred two (102) cycles in patients with unexplained RPL resulted in at least one euploid embryo transferred. Outcomes were compared by ovarian reserve test results, with diminished ovarian reserve (DOR) defined as a cycle day 3 FSH >10 IU/mL and/or antimüllerian hormone <1 ng/mL. INTERVENTION(S): In vitro fertilization with blastocyst biopsy and aneuploidy screening of all 23 chromosome pairs. MAIN OUTCOME MEASURE(S): Rate of aneuploidy in blastocysts and incidence of IVF cycles with no transfer owing to no euploid blasts. RESULT(S): Patients with DOR had a higher percentage of aneuploid blastocysts (57% vs 49%) and a higher incidence of no euploid embryos to transfer (25% vs 13%). The higher rate of aneuploidy in blastocysts was most significant in patients aged <38 years (67% vs 53%). Implantation rates after transfer of euploid blastocysts were similar (61% compared with 59%), and miscarriage rates were low (14% and 10%). CONCLUSION(S): Unexplained RPL patients with DOR have a higher percentage of aneuploid blastocysts and risk of no euploid embryo to transfer compared with unexplained RPL patients with normal ovarian reserve testing. The difference is most significant in patients aged <38 years. Patients with RPL and DOR with euploid embryo transferred had similar outcomes compared with patients with RPL and normal ovarian reserve testing.

Human trophoblast progenitors: where do they reside?

In humans, very little is known about the factors that regulate trophoblast (TB) specification, expansion of the initial TB population, and formation of the cytotrophoblast (CTB) populations that populate the chorionic villi. The absence of human trophoblast progenitor cell (hTPC) lines that can be propagated in vitro has been a limiting factor. Because attempts to derive TB stem cells from the trophectoderm of the human blastocyst have so far failed, investigators use alternative systems as cell culture models including TBs derived from human embryonic stem cells (hESCs), immortalized CTBs, and cell lines established from TB tumors. Additionally, the characteristics of mature TBs have been extensively studied using primary cultures of CTBs and explants of placental chorionic villi. However, none of these models can be used to study TB progenitor self-renewal and differentiation. Furthermore, the propagation of human TB progenitors from villous CTBs (vCTBs) has not been achieved. The downregulation of key markers of cell cycle progression in vCTBs by the end of the first trimester of pregnancy may indicate that these cells are not a source of human TB progenitors later in pregnancy. In contrast, mesenchymal cells of the villi and chorion continue to proliferate until the end of pregnancy. We recently reported isolation of continuously self-renewing hTPCs from chorionic mesenchyme and showed that they differentiated into the mature TB cell types of the villi, evidence that they can function as TB progenitors. This new cell culture model enables a molecular analysis of the seminal steps in human TB differentiation that have yet to be studied in humans. In turn, this information can be used to trace the origins of pregnancy complications that are associated with faulty TB growth and differentiation.

Serum unconjugated bisphenol A concentrations in men may influence embryo quality indicators during in vitro fertilization.

Here we assess bisphenol A (BPA) in couples undergoing in vitro fertilization (IVF) and indicators of embryo quality; embryo cell number (ECN) and embryo fragmentation score (EFS). Twenty-seven couples provided serum on the day of oocyte retrieval. Unconjugated BPA was measured by HPLC with Coularray detection. Odds ratios (OR) were generated using ordinal logistic regression including female and male BPA concentrations, age and race, and day of embryo transfer for ECN. Inverse associations are suggested for male BPA with ECN (OR=0.70, P=0.069), and EFS (OR=0.54, P=0.009), but not for women. Male BPA exposure may affect embryo quality during IVF.

Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization.

OBJECTIVE: To investigate associations between serum bisphenol A (BPA) concentrations and follicular response to exogenous ovary stimulation. DESIGN: Fasting serum was prospectively collected on the day of oocyte retrieval and assessed for unconjugated BPA using high-performance liquid chromatography with Coularray detection. Multivariable linear regression and negative binomial regression were used to assess associations between concentrations of BPA and outcome measures. Models were adjusted for race/ethnicity, antral follicle count at baseline, and cigarette smoking. SETTING: A reproductive health center. PATIENT(S): Forty-four women undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Peak E(2) level and the number of oocytes retrieved during IVF. RESULT(S): The median unconjugated serum BPA concentration is 2.53 ng/mL (range = 0.3-67.36 ng/mL). Bisphenol A is inversely associated with E(2) (ß = -0.16; 95% confidence interval = -0.32, 0.01), as well as with E(2) normalized to the number of mature-sized follicles at the hCG trigger (ß = -0.14; 95% confidence interval = -0.24, -0.03). No association is observed for BPA and the number of oocytes retrieved (adjusted risk ratio = 0.95; 95% confidence interval = 0.82, 1.10). CONCLUSION(S): Bisphenol A is associated with a reduced E(2) response during IVF. Although limited by the preliminary nature of this study, these results merit confirmation in a future comprehensive investigation.

Follicle-stimulating hormone administered at the time of human chorionic gonadotropin trigger improves oocyte developmental competence in in vitro fertilization cycles: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine whether an additional follicle-stimulating hormone (FSH) bolus administered at the time of the human chorionic gonadotropin (hCG) trigger can improve the developmental competence of the oocyte. DESIGN: Randomized, double-blind, placebo-controlled, clinical trial. SETTING: Academic medical center. PATIENT(S): Women undergoing a long agonist suppression in vitro fertilization (IVF) protocol for treatment of infertility. INTERVENTION(S): FSH bolus at time of hCG trigger versus placebo. MAIN OUTCOME MEASURE(S): Primary outcome; fertilization; secondary outcomes: oocyte recovery, implantation rate, and clinical and ongoing pregnancy/live birth rates. RESULT(S): A total of 188 women (mean age: 36.2 years; range: 25 to 40 years) were randomized. Fertilization (2PN/#oocyte) was statistically significantly improved in the treatment arm (63% vs. 55%) as was the likelihood of oocyte recovery (70% vs. 57%). There was no statistically significant difference in clinical pregnancy rate (56.8% vs. 46.2%) or ongoing/live birth rate (51.6% vs. 43.0%). CONCLUSION(S): Improvements in IVF success rates have largely been due to optimization of embryo culture and stimulation protocols; less attention has been directed toward methods to improve induction of final oocyte maturation. This was the first randomized, double-blind, placebo-controlled trial to modify the ovulation trigger to improve oocyte competence, as demonstrated by the statistically significant improvement in fertilization.

Physical activity in women with polycystic ovary syndrome: prevalence, predictors, and positive health associations.

OBJECTIVE: The purpose of this study was to describe the prevalence and predictors of physical activity in women with polycystic ovary syndrome (PCOS) and to explore the potential health benefits that are associated with physical activity in this population. STUDY DESIGN: This was a cross-sectional assessment of 150 women with PCOS. Active women (those who met Department of Health and Human Services [DHHS] guidelines for exercise) were compared with inactive women with regards to demographic and psychosocial variables and health characteristics. RESULTS: Fifty-nine percent (88/150 women) met the DHHS guidelines for physical activity. Active women were more likely than inactive women to be nulliparous (64.1% vs 40.0%; P = .04) and white (71.6% vs 42.6%; P = .0004). Inactive women were more likely to have mild depression (adjusted odds ratio, 2.2; 95% confidence interval, 1.01-4.79; P = .048). CONCLUSION: Women with PCOS who met the DHHS guidelines for physical activity were more likely to enjoy a variety of health benefits. Our findings identify several groups that are at risk for inadequate physical activity.

Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization.

Bisphenol A (BPA) is an endocrine disruptor with estrogenic properties that can adversely affect meiotic spindle assemblies. Our data indicate that BPA exposure in female patients may interfere with oocyte quality during IVF, as suggested by the inverse association between serum unconjugated BPA concentration and normal fertilization.

Asian ethnicity and poor outcomes after in vitro fertilization blastocyst transfer.

OBJECTIVE: To estimate the effect of ethnicity on in vitro fertilization (IVF) outcomes after blastocyst transfer. METHODS: We conducted a review of fresh blastocyst transfer IVF cycles from January 1, 2005, to December 31, 2006. Data collection included demographic information, infertility history, treatment protocol details, and treatment outcomes. Statistics were performed using the Student t test and chi2 test. To establish the independent contribution of Asian ethnicity, a multivariable logistic regression analysis was performed. RESULTS: We reviewed 180 blastocyst transfer cycles among white (62%) and Asian (38%) women. The groups were similar in most baseline characteristics. Asian women, however, had a lower body mass index (22.6 compared with 24.2, P=.02), were more likely to be nulligravid (53% compared with 35%, P=.03), and were more likely to have had at least one prior IVF cycle (37% compared with 20%, P=.02) The groups were similar in treatment characteristics, number of oocytes retrieved, fertilization rate, and number of blastocysts transferred. However, Asian women had a thicker endometrial lining (10.9 compared with 10.2, P=.02). Despite these similarities, Asian women had a lower implantation rate (28% compared with 45%, P=.01), clinical pregnancy rate (43% compared with 59%, P=.03), and live birthrate (31% compared with 48%, P=.02). In multivariable analysis, the decreased live birthrate among Asian women persisted (adjusted odds ratio 0.48, 95% confidence interval 0.24-0.96, P=.04). CONCLUSION: When compared with white women, Asian women have lower clinical pregnancy and live birthrates after blastocyst transfer.

Asian ethnicity in anonymous oocyte donors is associated with increased estradiol levels but comparable recipient pregnancy rates compared with Caucasians.

OBJECTIVE: To determine if differences exist in ovarian response and pregnancy rates between Asian and Caucasian donors. DESIGN: Retrospective cohort study. SETTING: University-based clinic. PATIENT(S): Anonymous oocyte donors of self-reported Asian (n=63) or Caucasian (n=156) ethnicity who began ovarian stimulation between February 2000 and March 2008 and their matched recipients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Recipient pregnancy rates and oocyte donor ovarian responsiveness. RESULT(S): Baseline characteristics were similar between Asian and Caucasian donors. Asian donors had peak serum estradiol levels that were 23% higher than their Caucasian counterparts (3715±220 vs. 3013±114 pg/mL). Adjusted estradiol levels per follicle measured and per oocyte retrieved were elevated in Asian donors (17% and 23% higher, respectively), and these differences were unchanged after adjusting for body mass index. No differences were noted in implantation rates (47.4% vs. 40.9%), clinical pregnancy rates (60.3% vs. 62.4%), or live-birth rates (55.5% vs. 59.9%) achieved using Asian vs. Caucasian oocyte donors. CONCLUSION(S): In contrast to autologous fresh in vitro fertilization cycles, Asian ethnicity is not associated with a lower pregnancy rate in recipient women using controlled hormone replacement when anonymous donor oocytes are used. Asian donors achieved statistically significantly higher serum estradiol levels during gonadotropin stimulation, suggesting an ethnic difference in steroid production and/or metabolism.

Follicular fluid steroid hormone levels are associated with fertilization outcome after intracytoplasmic sperm injection.

OBJECTIVE: To investigate the association between hormone levels from individual follicles and fertilization outcome among patients undergoing intracytoplasmic sperm injection (ICSI). Differences in concentrations of selected sex steroids and pituitary hormones in individual follicular aspirates between oocytes that fertilize successfully, those that fail to fertilize, and those that degenerate with ICSI were examined. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Women undergoing ovarian stimulation and ICSI. INTERVENTION(S): Follicular fluid was sampled by transvaginal ultrasound-guided aspiration of the hyperstimulated ovary. Each follicle was individually aspirated and collected. Intracytoplasmic sperm injection and subsequent embryo culture were performed using standard laboratory technique. Follicular fluid gonadotropin and steroid hormone levels were measured by immunoassay. MAIN OUTCOME MEASURE(S): Oocyte fertilization outcome with ICSI. RESULT(S): Oocytes that fertilized normally came from follicles with higher estradiol (adjusted odds ratio [AOR]=1.28) and testosterone (AOR=1.35) concentrations compared with those that degenerated with ICSI. Oocytes that fertilized normally also came from follicles with higher estradiol (AOR=1.14) and progesterone (AOR=1.09) concentrations compared with those that failed to fertilize. CONCLUSION(S): The hormonal profile of the follicular fluid yielding a degenerative egg or an egg that fails to fertilize is different from that resulting in normal fertilization. Higher follicular fluid estradiol may be a marker for oocytes that will fertilize normally with ICSI.

Poor prognosis with in vitro fertilization in Indian women compared to Caucasian women despite similar embryo quality.

BACKGROUND: Disease prevalence and response to medical therapy may differ among patients of diverse ethnicities. Poor outcomes with in vitro fertilization (IVF) treatment have been previously shown in Indian women compared to Caucasian women, and some evidence suggests that poor embryo quality may be a cause for the discrepancy. In our center, only patients with the highest quality cleavage stage embryos are considered eligible for extending embryo culture to the blastocyst stage. We compared live birth rates (LBR) between Indian and Caucasian women after blastocyst transfer to investigate whether differences in IVF outcomes between these ethnicities would persist in patients who transferred similar quality embryos. METHODOLOGY/PRINCIPAL FINDINGS: In this retrospective cohort analysis, we compared IVF outcome between 145 Caucasians and 80 Indians who had a blastocyst transfer between January 1, 2005 and June 31, 2007 in our university center. Indians were younger than Caucasians by 2.7 years (34.03 vs. 36.71, P = 0.03), were more likely to have an agonist down regulation protocol (68% vs. 43%, P<0.01), and were more likely to have polycystic ovarian syndrome (PCOS), although not significant, (24% vs. 14%, P = 0.06). Sixty eight percent of Indian patients had the highest quality embryos (4AB blastocyst or better) transferred compared to 71% of the Caucasians (P = 0.2). LBR was significantly lower in the Indians compared to the Caucasians (24% vs. 41%, P<0.01) with an odds ratio of 0.63, (95%CI 0.46-0.86). Controlling for age, stimulation protocol and PCOS showed persistently lower LBR with an adjusted odds ratio of 0.56, (95%CI 0.40-0.79) in the multivariate analysis. CONCLUSIONS/SIGNIFICANCE: Despite younger age and similar embryo quality, Indians had a significantly lower LBR than Caucasians. In this preliminary study, poor prognosis after IVF for Indian ethnicity persisted despite limiting analysis to patients with high quality embryos transferred. Further investigation into explanations for ethnic differences in reproduction is needed.

Asian ethnicity is associated with decreased pregnancy rates following intrauterine insemination.

Asian ethnicity has been associated with decreased pregnancy outcomes in patients undergoing IVF. The objective of this study was to determine if a difference exists in pregnancy rates between Asian and Caucasian patients undergoing intrauterine insemination (IUI). A retrospective cohort of Asian and Caucasian patients treated with IUI between December 2002 and 2006 was analysed, including 2327 IUI cycles among 814 patients. Baseline characteristics were similar between Asian and Caucasian women. A significantly greater proportion of Asians (43.9%) presented for treatment after more than 2 years of infertility compared with Caucasians (24.6%) (P < 0.0001). Unadjusted analysis showed a trend towards decreased pregnancy rates associated with Asian ethnicity (odds ratio (OR) 0.71, 95% CI 0.50-1.01, not significant). Age, stimulation protocol, differences in gravity and parity, and duration of infertility did not account for this difference (adjusted OR 0.68, 95% CI 0.47-0.98, P = 0.039). Asian ethnicity is associated with lower pregnancy rates in IUI treatment. The increased duration of infertility in Asians does not explain the reduced pregnancy rates.

The effect of follicular fluid hormones on oocyte recovery after ovarian stimulation: FSH level predicts oocyte recovery.

BACKGROUND: Ovarian stimulation for assisted reproductive technology (ART) overcomes the physiologic process to develop a single dominant follicle. However, following stimulation, egg recovery rates are not 100%. The objective of this study is to determine if the follicular fluid hormonal environment is associated with oocyte recovery. METHODS: This is a prospective study involving patients undergoing ART by standard ovarian stimulation protocols at an urban academic medical center. A total of 143 follicular fluid aspirates were collected from 80 patients. Concentrations of FSH, hCG, estradiol, progesterone, testosterone and prolactin were determined. A multivariable regression analysis was used to investigate the relationship between the follicular fluid hormones and oocyte recovery. RESULTS: Intrafollicular FSH was significantly associated with oocyte recovery after adjustment for hCG (Adjusted odds ratio (AOR) = 1.21, 95%CI 1.03-1.42). The hCG concentration alone, in the range tested, did not impact the odds of oocyte recovery (AOR = 0.99, 95%CI 0.93-1.07). Estradiol was significantly associated with oocyte recovery (AOR = 0.98, 95% CI 0.96-0.99). After adjustment for progesterone, the strength of association between FSH and oocyte recovery increased (AOR = 1.84, 95%CI 1.45-2.34). CONCLUSION: The relationship between FSH and oocyte recovery is significant and appears to work through mechanisms independent of the sex hormones. FSH may be important for the physiologic event of separation of the cumulus-oocyte complex from the follicle wall, thereby influencing oocyte recovery. Current methods for inducing the final stages of oocyte maturation, with hCG administration alone, may not be optimal. Modifications of treatment protocols utilizing additional FSH may enhance oocyte recovery.

Predictors of occult neoplasia in women undergoing risk-reducing salpingo-oophorectomy.

OBJECTIVE: The purpose of this study was to define the rate of neoplasia in prophylactic surgical specimens with the use of a careful surgical and pathologic protocol in a prospective study of high-risk women who were undergoing risk-reducing salpingo-oophorectomy. Outcomes of interest were neoplasia that was identified in surgical specimens and clinical outcomes of women who were undergoing risk-reducing salpingo-oophorectomy. We hypothesized that older age and having a BRCA1 mutation would be predictors for tubal or ovarian neoplasia and that a careful surgical and pathologic protocol would lead to a low rate of subsequent primary peritoneal cancer. STUDY DESIGN: A prospective tissue and research database enrolled patients who underwent risk-reducing salpingo-oophorectomy for prevention of ovarian cancer. Clinical and pathologic data were extracted for those patients after the initiation of a defined surgical and pathologic protocol in 1999. RESULTS: One hundred thirteen women met the high-risk criteria; 40 of the women (45%) who were tested had a deleterious mutation in BRCA1, and 22 women (25%) had a mutation in BRCA2. Seven women had ovarian or tubal neoplasia (6.2%). One woman had occult endometrial cancer. Age > or =45 years and having a BRCA1 or BRCA2 mutation were significant predictors of occult neoplasia. Two patients with neoplasia that was identified at risk-reducing salpingo-oophorectomy experienced recurrence. Three patients with BRCA1 mutations have subsequent new diagnoses of breast cancer. No patients had primary peritoneal cancer after risk-reducing salpingo-oophorectomy. CONCLUSION: Age > or =45 years and mutations in BRCA1 or BRCA2 predict occult neoplasia in women who undergo risk-reducing salpingo-oophorectomy. A thorough pathologic and surgical protocol at the time of risk-reducing salpingo-oophorectomy may improve the risk of subsequent primary peritoneal cancer.