Arcuate uterus: is there an impact on in vitro fertilization outcomes after euploid embryo transfer?

OBJECTIVE: To study the impact of the arcuate uterus on euploid blastocyst-stage embryo transfer outcomes after comprehensive chromosomal screening (CCS). DESIGN: Controlled retrospective trial. SETTING: Tertiary care assisted reproduction technology (ART) center. PATIENT(S): Consecutive patients undergoing in vitro fertilization and euploid embryo transfer after CCS during 2014. INTERVENTION(S): Ultrasound examinations and office hysteroscopy; array comparative genomic hybridization to perform CCS after a trophectoderm biopsy. MAIN OUTCOME MEASURE(S): Implantation and live-birth rates. RESULT(S): Patients were divided into two groups based on the presence (group 1) or absence (group 2) of arcuate uterus. Exclusion criteria were donor oocytes, evidence of other endometrial cavitary abnormalities, prior uterine surgery, and arcuate uterus <4 mm. Group 1 included 78 patients with arcuate uterus of mean depth 5.43 ± 1.81 mm (range: 4-9.5 mm) undergoing 83 transfer cycles. Group 2 included 354 controls undergoing 378 transfer cycles. There were no differences between the groups in baseline characteristics or mean number of euploid embryos transferred. Cycle outcomes were similar between the two groups: rates of implantation (63.7% vs. 65.4%), live birth (68.67% vs. 67.81%), biochemical pregnancy (8.4% vs. 7.65%), and spontaneous abortion (4.8% vs. 4.27%). CONCLUSION(S): Arcuate uterus has no impact on ART outcomes after euploid embryo transfer subsequent to CCS, so arcuate uterus should be considered an incidental finding without an indication for surgical resection.

GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression.

Prolonged gonadotrophin-releasing hormone agonist (GnRHa) administration before IVF with fresh embryo transfer to patients with endometriosis or aberrant endometrial integrin expression (-integrin) improves outcomes but may suppress ovarian response and prevents elective cryopreservation of all embryos. This retrospective cohort pilot study evaluates freeze-all cycles with subsequent prolonged GnRHa before embryo transfer in these populations. Patients from 2010 to 2015 who met inclusion criteria and received a long-acting GnRHa every 28 days twice before FET were evaluated. A subset underwent comprehensive chromosomal screening (CCS) after trophectoderm biopsy. Three groups were identified: Group 1: + CCS, +endometriosis (20 patients, 20 transfers); Group 2: +CCS, -integrin (12 patients, 13 transfers); Group 3: no CCS, +endometriosis or -integrin (10 patients, 12 transfers); Group 4: all transfers after CCS for descriptive comparison only (n = 2809). Baseline characteristics were similar among Groups 1-3 except that the mean surgery to oocyte aspiration interval was longer for Group 1 than Group 3. Implantation and ongoing pregnancy rates were statistically similar among the three groups and compared favourably to Group 4. A non-significant trend towards improved outcomes was noted in Group 1. Prolonged GnRHa after freeze-all in these patients avoids excessive ovarian suppression and results in excellent outcomes.

Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness?

OBJECTIVE: To evaluate the effects of methotrexate (MTX) on the future fertility of women undergoing IVF by comparing ovarian reserve and ovarian responsiveness in the IVF cycle before and after an ectopic pregnancy (EP) treated with MTX. DESIGN: Retrospective cohort study. SETTING: Private reproductive endocrinology and infertility practice. PATIENT(S): Sixty-six women undergoing IVF before and after receiving MTX for an EP. INTERVENTION(S): Methotrexate administration and ovarian stimulation. MAIN OUTCOME MEASURE(S): Markers of ovarian reserve (day 3 FSH, antral follicle count), measures of ovarian responsiveness (duration of stimulation, peak E2 level, total dose of gonadotropins, number of oocytes retrieved, fertilization rate), and time from MTX administration to subsequent IVF cycle. RESULT(S): There were no differences after MTX administration in body mass index (BMI), FSH, or antral follicle count. A greater dose of gonadotropins was used in the cycle after MTX, but there were no differences in numbers of oocytes retrieved or high quality embryos transferred. As expected, there was a slight increase in age in the subsequent IVF cycle. The pregnancy rates (PR) were comparable to the average PRs within the practice when combining all age groups. CONCLUSION(S): Methotrexate remains the first line of therapy for medical management of asymptomatic EP and does not compromise ovarian reserve, ovarian responsiveness, or IVF success in subsequent cycles.

Association of abnormal ovarian reserve parameters with a higher incidence of aneuploid blastocysts.

OBJECTIVE: To estimate the relationship between hormonal parameters of diminished ovarian reserve and the incidence of aneuploid blastocysts. METHODS: This prospective cohort trial was performed in a private in vitro fertilization clinic. Three hundred seventy-two patients underwent in vitro fertilization with blastocyst biopsy and aneuploidy screening of all 23 chromosome pairs. Patients were divided into groups based on baseline hormonal ovarian reserve. Group 1 included normal ovarian reserve (n=279) and group 2 included diminished ovarian reserve with day 2 or 3 follicle-stimulating hormone (FSH) more than 10 milli-international units/mL, antimüllerian hormone 1 ng/mL or less (n=93), or both. Patients with diminished ovarian reserves were further subdivided into three groups. Group A included FSH more than 10 milli-international units and antimüllerian hormone 1 ng/mL or less (n=25); group B included FSH more than 10 milli-international units/mL and antimüllerian hormone more than 1 ng/mL (n=34); and group C included antimüllerian hormone 1 ng/mL or less and day 3 FSH less than 10 milli-international units/L (n=34). RESULTS: Group 2 (diminished ovarian reserve) had a higher percentage of aneuploid blastocysts (66% compared with 51.7%; P<.05) and all aneuploid blastocyst cycles (35.1% compared with 14.3%; P<.001) than group 1 (normal ovarian reserve). However, implantation rates after transfer of euploid blastocysts were similar (69% compared with 61.7%; not significant). The highest percentage of aneuploid blastocysts among diminished ovarian reserve patients was in group A (abnormal FSH and antimüllerian hormone) compared with groups B and C (77.2% compared with 58.5% compared with 58.8%; P<.05). Implantation rates also were no different among the diminished ovarian reserve subgroups (68% compared with 71% compared with 66.7%; not significant). CONCLUSIONS: Infertility patients with hormonal evidence of diminished ovarian reserve have a significantly higher percentage of aneuploid blastocysts. The combination of abnormal serum FSH and antimüllerian hormone correlated with the greatest rate of embryonic aneuploidy. Regardless of ovarian reserve parameters, transfer of euploid blastocysts resulted in equivalent implantation potential. LEVEL OF EVIDENCE: II.

Does endometrial integrin expression in endometriosis patients predict enhanced in vitro fertilization cycle outcomes after prolonged GnRH agonist therapy?

OBJECTIVE: To determine whether endometrial expression of the integrin alpha(v)beta(3) vitronectin can predict which endometriosis patient subgroup will benefit from pre-IVF cycle prolonged GnRH agonist (GnRHa) therapy. DESIGN: Prospective randomized institutional review board approved pilot trial. SETTING: Private assisted reproductive technology program. PATIENT(S): IVF candidates with regular menses, surgically confirmed endometriosis, and normal ovarian reserve. INTERVENTION(S): All patients underwent endometrial biopsy 9 to 11 days post-LH surge to evaluate alpha(v)beta(3) integrin expression. Patients were randomized either to receive depot leuprolide acetate 3.75 mg every 28 days for three doses before controlled ovarian hyperstimulation (COH) or to proceed directly to COH and IVF. Group 1: integrin-positive controls (N = 12); group 2: integrin-positive administered prolonged GnRHa (N = 8). Group A: integrin-negative controls (N = 7); group B: integrin-negative administered prolonged GnRHa (N = 9). MAIN OUTCOME MEASURE(S): COH responses, ongoing pregnancy and implantation rates. RESULTS: There were no significant effects of GnRH agonist treatment in either of the integrin expression strata regarding ongoing pregnancy or implantation rates, although these outcomes were more frequent in group 2 vs. 1 (62.5% vs. 41.6% and 35% vs. 20.6%, respectively). This effect may have because of limited sample size. The value of a negative integrin biopsy in predicting an ongoing pregnancy after prolonged GnRH agonist therapy was only 44.4%. CONCLUSION(S): Endometrial alpha(v)beta(3) integrin expression did not predict which endometriosis patients would benefit from prolonged GnRHa therapy before IVF.

Converse regulatory functions of estrogen receptor-alpha and -beta subtypes expressed in hypothalamic gonadotropin-releasing hormone neurons.

Estradiol (E(2)) acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion. However, the extent to which these actions are mediated by estrogen receptors (ERs) expressed in GnRH neurons has been controversial. In this study, Single-cell RT-PCR revealed the expression of both ERalpha and ERbeta isoforms in cultured fetal and adult rat hypothalamic GnRH neurons. Both ERalpha and ERbeta or individual ERs were expressed in 94% of cultured fetal GnRH neurons. In adult female rats at diestrus, 68% of GnRH neurons expressed ERs, followed by 54% in estrus and 19% in proestrus. Expression of individual ERs was found in 24% of adult male GnRH neurons. ERalpha exerted marked G(i)-mediated inhibitory effects on spontaneous action potential (AP) firing, cAMP production, and pulsatile GnRH secretion, indicating its capacity for negative regulation of GnRH neuronal function. In contrast, increased E(2) concentration and ERbeta agonists increase the rate of AP firing, GnRH secretion, and cAMP production, consistent with ERbeta-dependent positive regulation of GnRH secretion. Consonant with the coupling of ERalpha to pertussis toxin-sensitive G(i/o) proteins, E(2) also activates G protein-activated inwardly rectifying potassium channels, decreasing membrane excitability and slowing the firing of spontaneous APs in hypothalamic GnRH neurons. These findings demonstrate that the dual actions of E(2) on GnRH neuronal membrane excitability, cAMP production, and GnRH secretion are mediated by the dose-dependent activation of ERalpha and ERbeta expressed in hypothalamic GnRH neurons.

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.

Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome.

BACKGROUND: Elevated estradiol (E(2)) levels predispose to development of ovarian hyperstimulation syndrome (OHSS). Since GnRH antagonist is associated with a reduction in E(2) levels, we hypothesized that GnRH-antagonist treatment of women down-regulated with GnRH agonist who are at risk of OHSS might reduce E(2) levels and avoid cycle cancellation. METHODS: Retrospective study in a university-based assisted reproduction technology (ART) programme in 87 patients treated with long luteal (LL) or microdose flare (MDF) with ovarian hyperresponse and 87 control patients without ovarian hyperresponse. GnRH-antagonist (ganirelix acetate) treatment was started and leuprolide acetate discontinued in women who failed to respond to a reduction in gonadotrophin dosage. RESULTS: In the treatment group, there was a significant, reproducible reduction in serum E(2) levels. Mean E(2) at the start of ganirelix treatment was 4219.8 pg/ml and decreased in 24 h to 2613.7 pg/ml (36.7%; P < 0.001). An average of 24.9 +/- 8.8 oocytes were obtained at retrieval and an average of 19.1 +/- 8.0 were metaphase II (79.2%). Fertilization occurred in 13.9 +/- 8.1 embryos (72.8%). In this high risk group, two cases of severe OHSS (2.3%) occurred. The ongoing pregnancy rate was 51.8%. Compared with the control group, there were no statistically significant differences in the rate of oocyte recovery, oocyte maturity, 2PN rate, fertilization, cancellation, OHSS or pregnancy. CONCLUSIONS: GnRH-antagonist treatment of women pretreated with GnRH agonist rapidly reduced circulating serum E(2) without adversely affecting oocyte maturation, fertilization rates or embryo quality and resulted in a high pregnancy rate in this subgroup of patients at risk of OHSS.

Endometriosis and the appendix: a case series and comprehensive review of the literature.

OBJECTIVE: To report the prevalence of appendiceal disease in women with chronic pelvic pain undergoing laparoscopy for possible endometriosis, summarize the literature, and more accurately estimate the prevalence of endometriosis of the appendix. DESIGN: Prospective case series and literature review. SETTING: Academic research institute. PATIENT(S): One hundred thirty-three patients with chronic pelvic pain and possible endometriosis undergoing laparoscopy. INTERVENTION(S): History, physical exam, and abdominopelvic laparoscopy. Endometriosis and adhesions were excised using selective Nd:YAG contact laser trabeculoplasty and pathologically evaluated. Only patients with visible abnormalities involving the appendix were treated via concurrent laparoscopic appendectomy. MAIN OUTCOME MEASURE(S): Appendiceal abnormalities at laparoscopy. RESULT(S): Of 133 patients, 13 had a previous appendectomy with unknown pathology. Of the remaining 120 patients, 109 reported right lower quadrant pain. Of this subgroup, six patients had appendiceal pathology: four with pathology-confirmed endometriosis, one with Crohn's disease suspected at laparoscopy, and one with chronic appendicitis. The prevalence of appendiceal endometriosis in patients with biopsy-proven endometriosis (n = 97) or with right lower quadrant pain (n = 109) was 4.1% and 3.7%, respectively. This rate was similar to the 2.8% prevalence confirmed by literature review in patients with endometriosis but was much higher than that reported in all patients (0.4%). CONCLUSION(S): Appendiceal endometriosis, while relatively uncommon in patients with endometriosis, is rare in the general population. In patients with right lower quadrant or pelvic pain, the appendix should be inspected for endometriosis and evidence of nongynecologic disease.

Treatment with gonadotropin-releasing hormone (GnRH) antagonists in women suppressed with GnRH agonist may avoid cycle cancellation in patients at risk for ovarian hyperstimulation syndrome.

Forty-seven patients at high risk for ovarian hyperstimulation syndrome because of markedly elevated serum E2 levels on either long-luteal or microdose flare leuprolide acetate regimens were treated with ganirelix acetate. Despite being pretreated with GnRH agonist and without withholding gonadotropins, serum E2 decreased by 49.5% and 41.0% of pretreatment values (long luteal and microdose flare, respectively) after initiation of ganirelix, and 68.1% of the patients became pregnant.