Long-term imatinib diminishes ovarian reserve and impacts embryo quality.

PURPOSE: Tyrosine kinase inhibitors (TKIs) such as imatinib are commonly used chemotherapeutics, but the effects of long-term treatments on reproductive outlook for cancer survivors are unknown. The purpose of this study was to examine the effects of long-term imatinib treatments on follicle development and embryo quality. Since prospective studies are not possible in healthy humans, we have incorporated a commonly used mouse model. METHODS: Adult female mice were treated with daily IP injections of imatinib for 4-6 weeks. Liquid chromatography-mass spectrometry was used to measure imatinib in serum and ovarian tissues. At the end of treatments, females were superovulated and mated to yield fertilized embryos. Oocytes and embryos were collected from oviducts, assessed for development by microscopy, and fertilized embryos were cultured in vitro. Blastocysts were fixed and stained for differential cell counts. RESULTS: Long-term imatinib treatments caused a shift in follicle development, with imatinib-treated females having fewer primordial follicles, but an increase in primary and secondary follicles (P < 0.05). There was no effect on ovulation or fertilization rates. However, blastocysts from imatinib-treated females had fewer total cells (P < 0.05) and a significant shift from inner cell mass to increased trophectoderm cells. CONCLUSION: This pilot study indicates that long-term TKI treatments may have significant impact on ovarian reserve and embryo developmental capacity. More studies are needed in other model systems to determine the long-term impact of TKIs in patients. Knowing the potential effects of chemotherapeutics on reproductive outlook is critical for quality of life and more research is needed.

Soluble LH-HCG receptor and oestradiol as predictors of pregnancy and live birth in IVF.

RESEARCH QUESTION: Circulating soluble LH-HCG receptor (sLHCGR) is a first-trimester marker for screening pregnancy pathologies and predicts premature or multiple births before fertility treatment. Oestradiol per oocyte at ovulation induction predicts IVF treatment outcomes. We asked whether sLHCGR levels are stable during fertility treatment and whether, alone or with oestradiol, they could improve prediction of fertility treatment outcomes. DESIGN: Serum sLHCGR, anti-Müllerian hormone [AMH] and oestradiol were measured in patients undergoing IVF. Antral follicle count before ovarian stimulation and oocyte yield were used to establish sLHCGR- oocyte ratio (SOR), sLHCGR- antral follicle ratio (SAR), oestradiol at trigger per oocyte (oestradiol-oocyte ratio [EOR]) and oestradiol at trigger per antral follicle (oestradiol-antral follicle ratio [EAR]). RESULTS: The relatively stable sLHCGR was negatively related to AMH when oocyte yield was high. The sLHCGR levels were proportional (r = 0.49) to oestradiol at early cycle (day-3). Pregnancy and live birth were highest at low sLHCGR (≤1.0 pmol/ml) and SOR (≤ 0.1 pmol/ml/oocyte). A total of 86-89% of live births in IVF treatment were within the cut-off parameters of SAR and SOR (0.5 pmol/ml) and EAR and EOR (380 pg/ml). For failed pregnancy, age, SOR and EOR together had positive and negative predictive values of 0.841 and 0.703, respectively. CONCLUSIONS: sLHCGR levels are negatively related to AMH when oocyte yield is high. High early cycle sLHCGR is associated with elevated day-3 oestradiol. Low sLHCGR and SOR are indicators of increased clinical pregnancy and live birth rates. Patient age and SOR, combined with EOR, might improve prediction of IVF treatment outcomes.

Micro-RNAs involved in cellular proliferation have altered expression profiles in granulosa of young women with diminished ovarian reserve.

PURPOSE: The study aims to determine differences in micro-RNA (miRNA) expression in granulosa (GC) and cumulus cells (CC) between young women with diminished ovarian reserve (DOR) or normal ovarian reserve (NOR). Secondary objective was to identify downstream signaling pathways that could ultimately indicate causes of lower developmental competence of oocytes from young women with DOR. METHODS: The method of the study is prospective cohort study. RESULTS: Of the miRNA, 125 are differentially expressed in GC between DOR and NOR. Only nine miRNA were different in CC; therefore, we focused analysis on GC. In DOR GC, miR-100-5p, miR-16-5p, miR-30a-3p, and miR-193a-3p were significantly downregulated, while miR-155-5p, miR-192-5p, miR-128-3p, miR-486-5p, miR130a-3p, miR-92a-3p, miR-17-3p, miR-221-3p, and miR-175p were increased. This pattern predicted higher cell proliferation in the DOR GC. The primary pathways include MAPK, Wnt, and TGFbeta. CONCLUSIONS: The miRNA pattern identified critical functions in cell proliferation and survival associated with DOR. GC in women with DOR seems to respond differently to the LH surge.

Perinatal outcomes after natural conception versus in vitro fertilization (IVF) in gestational surrogates: a model to evaluate IVF treatment versus maternal effects.

OBJECTIVE: To study the perinatal outcomes between singleton live births achieved with the use of commissioned versus spontaneously conceived embryos carried by the same gestational surrogate. DESIGN: Retrospective cohort study. SETTING: Academic in vitro fertilization center. PATIENT(S): Gestational surrogate. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pregnancy outcome, gestational age at birth, birth weight, perinatal complications. RESULT(S): We identified 124 gestational surrogates who achieved a total of 494 pregnancies. Pregnancy outcomes for surrogate and spontaneous pregnancies were significantly different (P<.001), with surrogate pregnancies more likely to result in twin pregnancies: 33% vs. 1%. Miscarriage and ectopic rates were similar. Of these pregnancies, there were 352 singleton live births: 103 achieved from commissioned embryos and 249 conceived spontaneously. Surrogate births had lower mean gestational age at delivery (38.8 ± 2.1 vs. 39.7 ± 1.4), higher rates of preterm birth (10.7% vs. 3.1%), and higher rates of low birth weight (7.8% vs. 2.4%). Neonates from surrogacy had birth weights that were, on average, 105 g lower. Surrogate births had significantly higher obstetrical complications, including gestational diabetes, hypertension, use of amniocentesis, placenta previa, antibiotic requirement during labor, and cesarean section. CONCLUSION(S): Neonates born from commissioned embryos and carried by gestational surrogates have increased adverse perinatal outcomes, including preterm birth, low birth weight, hypertension, maternal gestational diabetes, and placenta previa, compared with singletons conceived spontaneously and carried by the same woman. Our data suggest that assisted reproductive procedures may potentially affect embryo quality and that its negative impact can not be overcome even with a proven healthy uterine environment.

The role of angiogenic markers in adverse perinatal outcomes: fresh versus frozen embryo transfers.

PURPOSE: We aimed to investigate the angiogenic balance in fresh compared to frozen embryo transfers, and among neonates with adverse perinatal outcomes. METHODS: This was a retrospective cohort study. All IVF cycles resulting in a singleton live birth at a university academic fertility center from January 1, 2011, to December 31, 2013, were examined. Concentrations of sFLT-1 and PlGF were measured in previously frozen serum specimens collected during early gestation at approximately 5 weeks gestation. Patients completed an electronic survey to detail perinatal outcome. RESULTS: We identified 152 singleton live births (103 fresh, 49 frozen). Demographic characteristics were similar between the two groups. Ratios of sFlt-1:PlGF were not different between fresh and frozen transfers. Neonates from fresh cycles had a mean birth weight 202 g lighter (p = 0.01) than frozen cycles, after adjusting for gestational age. Among babies born with poor perinatal outcomes, there was a difference in sFlt-1:PlGF ratios after adjusting for race. In non-Asians, infants born small for gestational age (SGA) (< 10th percentile) had significantly higher sFLT-1:PLGF ratio, median ratio (0.21 vs 0.12, p = 0.016). CONCLUSIONS: Fresh transfers were associated with lower birth weight infants compared to frozen transfers. While there was no difference in sFlt-1:PlGF ratios between fresh and frozen transfers, these ratios were significantly lower in SGA infants, suggesting an imbalance in angiogenic markers during placentation.

A comparison of live birth rates and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos.

PURPOSE: Prior studies suggest that pregnancy outcomes after autologous oocyte cryopreservation are similar to fresh in vitro fertilization (IVF) cycles. It is unknown whether there are differences in pregnancy and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos. METHODS: This is a retrospective cohort study comparing pregnancy and perinatal outcomes between oocyte and embryo cryopreservation at a university-based fertility center. We included 42 patients and 68 embryo transfers in patients who underwent embryo transfer after elective oocyte preservation (frozen oocyte-derived embryo transfer (FOET)) from 2005 to 2015. We compared this group to 286 patients and 446 cycles in women undergoing cryopreserved embryo transfer (frozen embryo transfer (FET)) from 2012 to 2015. RESULTS: Five hundred fourteen transfer cycles were included in our analysis. The mean age was lower in the FOET vs FET group (34.3 vs 36.0 years), but there were no differences in ovarian reserve markers. Thawed oocytes had lower survival than embryos (79.1 vs 90.1%); however, fertilization rates were similar (76.2 vs 72.8%). In the FOET vs FET groups, clinical pregnancies were 26.5 and 30%, and live birth rates were 25 and 25.1%. Miscarriages were higher in the FET group, 8.1 vs 1.5%. There were no differences in perinatal outcomes between the two groups. The mean gestational age at delivery was 39.1 vs 38.6 weeks, mean birth weight 3284.2 vs 3161.1 gms, preterm gestation rate 5.9 vs 13.4%, and multiple gestation rate 5.9 vs 11.6%. CONCLUSIONS: In our study, live birth rates and perinatal outcomes were not significantly different in patients after oocyte and embryo cryopreservation.

Six-month and 1-year continuation rates following postpartum insertion of implants and intrauterine devices.

OBJECTIVE: Studies show immediate postpartum (PP) insertion increases use of contraceptive implants and intrauterine devices (IUDs). Our objective was to compare the satisfaction and continuation rates of the two types of devices at 6 months and 1 year following PP insertion. STUDY DESIGN: We enrolled 133 women in a prospective cohort study following immediate PP insertion of an implant or IUD at two academic hospitals during 8 months of 2011. Subjects completed an enrollment survey during hospital admission and a follow-up phone survey 6 months and 1 year PP. RESULTS: At 6 months PP, 72% of subjects provided follow-up information. Implant users were more likely to be using the originally-placed device (40/41, 98% vs. 45/55, 82%, p=0.02); nine women reported IUD expulsions. When accounting for replacement of expelled IUDs, IUD continuation at 6 months was 89% yielding similar continuation rates between groups (p=0.12). At 1 year PP, 51% provided follow-up. Of those, 82% still had a LARC method in place with similar continuation by device type (84% for implants, 81% for IUDs, p=0.96). Overall, satisfaction was similarly high in both groups. CONCLUSION: Due to IUD expulsion, implants had a higher continuation rate than IUDs six months following immediate PP insertion. After replacement of expelled IUDs, continuation and satisfaction were similar for both devices at 6 months and 1 year. IMPLICATIONS: Placement of implants and IUDs immediately PP can lead to high satisfaction. Despite early IUD expulsions, continuation rates were similar to those placed outside of the immediate PP period.

Predictive Value of Elevated LH/FSH Ratio for Ovulation Induction in Patients with Polycystic Ovary Syndrome.

OBJECTIVE: To assess the value of an elevated luteinizing hormone (LH)-to-follicle-stimulating hormone (FSH) ratio in predicting development of a dominant follicle when ovulation induction is implemented with clomiphene citrate (CC) or letrozole in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Retrospective review of 312 monitored cycles between 2007 and 2012. All patients met the diagnostic criteria set by the 2006 Androgen Excess-PCOS Society and had baseline LH and FSH levels drawn. Only ovulation induction with CC or letrozole was included. Primary outcome was development of a dominant follicle of ≥ 18 mm. RESULTS: The development of a dominant follicle was significantly associated with clinical pregnancy. The development of a dominant follicle was also higher in the letrozole group as compared to the CC group (87.6% [155/177] vs. 62.2% [84/135], p < 0.001). Furthermore, treatment with letrozole significantly increased the odds of forming a dominant follicle when LH/FSH ratio was ≥ 1 (odds ratio [OR] 7.69, CI 3.69-16.02). When LH/ FSH ratio was < 1, letrozole had no significant effect on dominant follicle development (OR of 3.63, CI 0.92-14.25). CONCLUSION: LH/FSH ratio ≥ 1 could be useful as a predictive tool to identify which subgroup of PCOS patients may be more successful in forming a dominant follicle when using letrozole as compared to CC.

Periurethral cystic mass misdiagnosed: a case report.

BACKGROUND: Periurethral cystic masses, including Skene's duct cyst and urethral diverticula, are rare and are often misdiagnosed for more common vulvovaginal cysts. Given their proximity to the urethra, correct diagnosis is needed for appropriate referral and surgical management to prevent complications, including fistula formation. CASE: A 36-year-old woman was diagnosed by her primary care physician with a Bartholin's gland cyst, which was confirmed on MRI. She was referred to a gynecologist for incision and drainage. However, on examination the cyst was noted to be more anterolateral on the vagina and more concerning for a Skene's duct cyst or a urethral diverticulum. She was referred to Urogynecology. The images were reviewed with the radiologist, who agreed that the lesion was more consistent with a Skene's duct cyst. She underwent successful excision of the cyst. The patient had an uncomplicated postoperative course and has normal bladder and urethral function. CONCLUSION: Although imaging modalities are useful to assist in diagnosis of vulvovaginal lesions, clinical examination finding is also key in distinguishing periurethral cystic masses from their more common vulvovaginal counterparts.

Cabergoline therapy for Cushing disease throughout pregnancy.

BACKGROUND: Cushing disease during pregnancy is rare and is associated with significant maternal and fetal morbidity and mortality. Transsphenoidal pituitary surgery is the first-line therapy; however, in cases of failed surgery or in patients who are not surgical candidates, medical therapy has been used to control symptoms. CASE: A 29-year-old woman with Cushing disease and a noncurative transsphenoidal pituitary surgery was successfully treated with cabergoline, a dopamine agonist. After approximately 1 year of therapy, she became pregnant. She was maintained on high-dose cabergoline throughout her pregnancy and had an uncomplicated antenatal course. She went into spontaneous labor at 38 weeks of gestation and delivered a healthy female neonate. CONCLUSION: Cabergoline can be used to manage Cushing disease successfully during pregnancy with an opportunity for a favorable outcome.

Hormonal variations in the vascularity of breast tissue.

OBJECTIVE: The purpose of this study was to determine whether there are sonographically detectable variations in breast glandularity and vascularity due to hormonal changes during the course of a normal menstrual cycle. METHODS: Gray scale and color and power Doppler sonographic evaluations were performed on 7 premenopausal patients over the course of 1 menstrual cycle. Progesterone and estradiol levels were measured from saliva collected from the patients. Vascularity was measured by mean color level, area covered by color pixels, and color-weighted fractional area. RESULTS: Of the 5 volunteers not taking oral contraceptives, 4 had peaks in vascularity correlating with midcycle peak hormonal levels (50%-320% from baseline) on power Doppler sonography. On color Doppler sonography, 3 of 5 patients also had peaks in vascularity (60%-190% from baseline). The 2 patients taking oral contraceptives did not have any peaks in vascularity. CONCLUSIONS: Vascularity changes in normal breast tissue that correlated with peak hormonal levels were detected in most of the volunteers. Therefore, hormonal variations in breast vascularity should be considered when evaluating breast lesions by sonography.

New 2-bromomethyl-8-substituted-benzo[c]chromen-6-ones. Synthesis and biological properties.

New 2-bromomethyl-8-substituted-benzo[c]chromen-6-ones have been synthesized and their bioactive properties have been evaluated on different enzymatic models: serine proteases (trypsin and alpha-chymotrypsin), HIV aspartyl protease, nitric oxide synthase and a panel of protein kinases. These new derivatives can provide upon chemical or enzymatic attack, very reactive quinonimine methide intermediates, which could be utilized for the design of enzyme inhibitors. We found that some of these new derivatives exhibit modest inhibitory activities on the studied enzyme models, but it could be improved after structure optimization.

MR imaging screening of the contralateral breast in patients with newly diagnosed breast cancer: preliminary results.

PURPOSE: To investigate the role of screening magnetic resonance (MR) imaging in the detection of synchronous contralateral breast cancer in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: Between January 1999 and July 2001, 182 patients with newly diagnosed breast cancer (after either core or excisional biopsy with positive or close margins of resection) underwent bilateral contrast material-enhanced MR imaging at 1.5 T with a dedicated bilateral breast multicoil array. The contralateral breast was imaged for cancer screening. Family history of breast cancer, index cancer histology, breast density, and age at diagnosis of first breast cancer were assessed as potential risk factors for synchronous contralateral breast cancer. RESULTS: Fifteen patients (8.2%) had a suspicious enhancing lesion depicted in the contralateral breast. Seven patients (3.8%) had malignant results: ductal carcinoma in situ (DCIS) in four, invasive ductal carcinoma with DCIS in two, and invasive ductal carcinoma in one. Eight patients (4.4%) had benign results: fibrocystic changes in four, atypical ductal hyperplasia in two, atypical lobular hyperplasia and focal lobular carcinoma in situ in one, and ductal hyperplasia in one. Six patients with negative MR findings underwent prophylactic mastectomy; no malignancy was found. No significant differences were noted among patients with true-positive (n = 7), false-positive (n = 8), or negative (n = 167) MR findings with regard to family history of breast cancer (P <.27), index cancer histology (P <.19), breast density (P <.34), or age at diagnosis of first breast cancer (P <.10). CONCLUSION: The preliminary results demonstrate the feasibility of using MR imaging of the breast in a screening role, specifically to evaluate the contralateral breast in patients with newly diagnosed breast cancer to detect mammographically and clinically occult synchronous breast cancer.