Assessing ovarian response: antral follicle count versus anti-Müllerian hormone.

Oocyte number and quality decline with age; however, fertility varies significantly even among women of the same age. Various measures have been developed to predict response to ovarian stimulation and reproductive potential. Evaluation of ovarian reserve can identify patients who may experience poor response or hyper-response to exogenous gonadotrophins and can aid in the personalization of treatment to achieve good response and minimize risks. In recent years, two key methods, antral follicle count (AFC), an ultrasound biomarker of follicle number, and the concentration of serum anti-Müllerian hormone (AMH), a hormone biomarker of follicle number, have emerged as preferred methods for assessing ovarian reserve. In this review, a live debate held at the American Society for Reproductive Medicine 2013 Annual Meeting is expanded upon to compare the predictive values, merits, and disadvantages of AFC and AMH level. An ovarian reserve measure without limitations has not yet been discovered, although both AFC and AMH have good predictive value. Published evidence, however, as well as the objectivity and potential standardization of AMH level and the convenience of testing any time throughout the menstrual cycle, leans towards AMH level becoming the gold-standard biomarker to evaluate ovarian reserve and predict ovarian response to stimulation.

Clinical impact of LH rises prior to and during ganirelix treatment started on day 5 or on day 6 of ovarian stimulation.

BACKGROUND: We sought to evaluate the incidence and clinical impact of luteinizing hormone (LH) rises prior to and during gonadotropin-releasing hormone (GnRH) antagonist treatment started on day 5 or 6 of ovarian stimulation with recombinant follicle-stimulating hormone (rFSH). METHODS: Pooled data from three trials with the GnRH antagonist ganirelix started on day 5 (n = 961) and from five trials with ganirelix started on day 6 (n = 1135) of ovarian stimulation with rFSH were retrospectively analyzed. RESULTS: The incidence of LH rises (LH ≥ 10.0 IU/L) prior to ganirelix treatment was 2.3% and 6.6% on ganirelix start days 5 and 6, respectively (P < 0.01). During ganirelix treatment this incidence was 1.2% and 2.3%, respectively (P = 0.06). Women with LH rise on day 5 or 6 had a higher ovarian response with more oocytes recovered, mean ± SD, 12.9 ± 8.5 versus no LH rise, 10.2 ± 6.4 (P < 0.01). In women with and without LH rise prior to ganirelix treatment the ongoing pregnancy rates were similar (26.0% vs 29.9%; odds ratio [OR], 0.89; 95% confidence interval [CI], 0.55-1.44). Women with LH rise during ganirelix treatment had a lower ovarian response with 7.5 ± 6.7 oocytes recovered versus no LH rise, 10.2 ± 6.4 (P = 0.02) and a tendancy for a lower chance of ongoing pregnancy (16.7% vs 29.9%; OR, 0.52; 95% CI, 0.21-1.26). CONCLUSIONS: The incidence of early and late LH rises was low but may be further reduced by initiating ganirelix on stimulation day 5 rather than on day 6. In contrast to women with an early LH rise, women with a late LH rise may have a reduced chance of ongoing pregnancy.

The relationship between pulsatile GnRH secretion and cAMP production in immortalized GnRH neurons.

In perifused immortalized GnRH neurons (GT1-7), simultaneous measurements of GnRH and cAMP revealed that the secretory profiles for both GnRH and cAMP are pulsatile. An analysis of GnRH and cAMP pulses in 16 independent experiments revealed that 25% of pulses coincide. Inversion of the peak and nadir levels was found in 33% and random relationship between GnRH and cAMP found in 42% of analyzed pulses. The random relation between GnRH and cAMP pulse resets to synchronous after an inverse relation between pulses occurred during the major GnRH release, indicating that GnRH acts as a switching mechanism to synchronize cAMP and GnRH release in perifused GT1-7 neurons. Activation of GnRH receptors with increasing agonist concentrations caused a biphasic change in cAMP levels. Low nanomolar concentrations increased cAMP production, but at high concentrations the initial increase was followed by a rapid decline to below the basal level. Blockade of the GnRH receptors by peptide and nonpeptide antagonists generated monotonic nonpulsatile increases in both GnRH and cAMP production. These findings indicate that cAMP positively regulates GnRH secretion but does not participate in the mechanism of pulsatile GnRH release.

Aneuploidy in abortuses following IVF and ICSI.

PURPOSE: To compare aneuploidy rates in first trimester pregnancy losses following IVF+/-ICSI. METHODS: A retrospective cohort analysis of karyotypes of abortuses following conventional IVF (n=159) and ICSI (n=196). RESULTS: 50.1% of losses were found to be cytogenetically abnormal among all patients undergoing IVF+/-ICSI. A significant increase in fetal aneuploidy rate was noted with increasing maternal age (<30 years=26.1% vs. 31 to 34 years.=38.2% vs. 35 to 39 years.=51.3% vs. >39 years.=65.9%). Aneuploidy rates were similar in the ICSI vs. conventional IVF groups (52.6% vs. 47.2% [p 0.31, RR 1.11, 95% CI 0.90, 1.38]). More sex chromosome anomalies were noted in the ICSI group. CONCLUSIONS: The aneuploidy rate in first trimester abortuses significantly increases with increasing maternal age. ICSI was not shown to significantly increase the aneuploidy rate. However, more sex chromosome anomalies were found among pregnancies resulting from ICSI.

Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial.

OBJECTIVE: To evaluate the benefit of next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) for embryo selection in frozen-thawed embryo transfer. DESIGN: Randomized controlled trial. SETTING: Not applicable. PATIENT(S): Women aged 25-40 years undergoing IVF with at least two blastocysts that could be biopsied. INTERVENTION(S): Randomization for single frozen-thawed embryo transfer with embryo selection based on PGT-A euploid status versus morphology. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) at 20 weeks' gestation per embryo transfer. RESULT(S): A total of 661 women (average age 33.7 ± 3.6 years) were randomized to PGT-A (n = 330) or morphology alone (n = 331). The OPR was equivalent between the two arms, with no significant difference per embryo transfer (50% [137/274] vs. 46% [143/313]) or per intention to treat (ITT) at randomization (41.8% [138/330] vs. 43.5% [144/331]). Post hoc analysis of women aged 35-40 years showed a significant increase in OPR per embryo transfer (51% [62/122] vs. 37% [54/145]) but not per ITT. CONCLUSION(S): PGT-A did not improve overall pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT. There was a significant increase in OPR per embryo transfer with the use of PGT-A in the subgroup of women aged 35-40 years who had two or more embryos that could be biopsied, but this was not significant when analyzed by ITT. CLINICAL TRIAL REGISTRATION NUMBER: NCT02268786.

Basal ovarian cysts and clomiphene citrate ovulation induction cycles.

OBJECTIVE: To evaluate the effect of simple basal ovarian cysts in patients undergoing infertility treatment with clomiphene citrate. To evaluate the effect of clomiphene citrate on pretreatment simple ovarian cysts. METHODS: Prospective cohort trial of 84 infertility patients undergoing ovulation induction with clomiphene citrate. Patients with basal ovarian cysts of 10 mm or greater (n = 42) were compared with patients without ovarian cysts (n = 42). The main outcome measure was ovulation determined by menstrual cycle day 21 progesterone level. Each patients with an ovarian cyst was also evaluated for persistence or resolution of the cyst in association with ovulation and cyst size. Pretreatment and posttreatment transvaginal ultrasound examinations were performed on all patients. RESULTS: Demographic data were similar among the groups. The mean ovarian cyst size was 17.4 +/- 5.8 mm. Patients in the ovarian cyst group were significantly less likely to ovulate (80.9% versus 97.6%, P < .05), but did not differ in pregnancy rate compared with patients without baseline ovarian cysts (4.8% versus 11.9%, P = .43). Persistent ovarian cysts occurred in 36.7% of the patients. The initial size of the cyst did not predict cyst persistence. CONCLUSION: According to these data, basal ovarian cysts significantly reduce ovulatory events in patients treated with clomiphene citrate. LEVEL OF EVIDENCE: II-2.

Characteristics of baseline ovarian cysts in clomiphene citrate ovulation cycles.

To evaluate the incidence and factors associated with ovarian cysts in infertile patients receiving clomiphene citrate (CC), we performed a retrospective cohort study involving 466 CC treatment cycles. Ovarian cysts are a common finding in patients presenting for CC, with approximately one in five patients having a baseline ovarian cyst >10 mm.

Effect of androgen levels on in vitro fertilization cycles.

Serum androgens have a negative correlation with some IVF stimulation parameters. Day 3 T levels

Prognostic use of mean ovarian volume in in vitro fertilization cycles: a prospective assessment.

OBJECTIVE: To determine the predictive value and to define prognostic threshold measurements for mean ovarian volume (MOV) in patients undergoing IVF. DESIGN: Prospective cohort analysis. SETTING: Tertiary care center. PATIENT(S): Two hundred sixty-seven patients. INTERVENTION(S): Transvaginal ultrasound before starting gonadotropins. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved, basal hormone levels, and cycle outcomes. RESULT(S): The MOV for the population was 4.78 +/- 2.6 cm(3) (range 0.9-21.1 cm(3)). The MOV significantly correlated with the majority of prestimulation and poststimulation IVF parameters. Threshold analysis demonstrated a lower pregnancy rate associated with a MOV of <2 cm(3) (31.6% vs. 55.6%). Threshold analysis revealed a trend toward higher cancellation rate associated with a MOV of <2 cm(3) (21.1% vs. 7.3%). CONCLUSION(S): Although MOV correlated with IVF stimulation parameters, its use as an adjunct in counseling patients during IVF appears to be of limited value. A MOV <2 cm(3) was associated clinically with a higher cancellation rate (21.1%) and a lower pregnancy rate (31.6%) in those cycles not cancelled. However, these values do not deviate far from the mean national IVF outcome rates. There was no absolute MOV that was predictive of pregnancy outcome or cycle cancellation.

A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles.

OBJECTIVE: To determine the predictive value and define threshold values for basal antral follicle count in patients undergoing IVF. DESIGN: Prospective cohort analysis. Tertiary care center. Two hundred eighty-nine patients. Transvaginal ultrasonography before starting gonadotropin administration. MAIN OUTCOME MEASURES: Number of oocytes retrieved, basal hormone levels, and cycle outcomes. RESULTS: Pregnant patients had significantly more antral follicles (13.8 +/- 7.5 vs. 12.4 +/- 10.0). Patients in whom cycles were canceled had significantly fewer antral follicles (7.6 +/- 4.8 vs. 13.7 +/- 8.8). Antral follicle count significantly correlated with most prestimulation and poststimulation IVF variables. Threshold analysis demonstrated a lower pregnancy rate (23.5% vs. 57.6%) and a higher cancellation rate (41% vs. 6.4%) associated with having four or fewer antral follicles. CONCLUSION(S): The basal antral follicle count identified patients who responded poorly to IVF stimulation. Having four or fewer antral follicles was associated with a high cancellation rate (41%) and, in patients without a cancelled cycle, a low pregnancy rate (23%). However, no antral follicle count absolutely predicted pregnancy or cycle cancellation.

Body mass index impacts in vitro fertilization stimulation.

The objective of the study was to prospectively determine if body mass index (BMI) is predictive of live birth rates in patients undergoing IVF. The prospective study enrolled 117 infertility patients with the primary outcome measure being IVF success rates. Mean BMI did not differ between patients with successful outcomes and those without successful outcomes. There was a significant positive correlation between BMI and the number of stimulated follicles (r = 0.19, P < .05). A significant negative correlation between BMI and ampules of gonadotropins used (r = -0.25, P < .01) and between BMI and days of stimulation (r = -0.19, P < .05) was noted. These data demonstrate that women with an elevated BMI produce more follicles, stimulate quicker, and require less gonadotropins during IVF. However, BMI did not have a significant effect on pregnancy outcome rates.

A GnRH agonist and exogenous hormone stimulation protocol has a higher live-birth rate than a natural endogenous hormone protocol for frozen-thawed blastocyst-stage embryo transfer cycles: an analysis of 1391 cycles.

OBJECTIVE: To compare embryo and birth data in cryopreserved-thawed blastocyst-stage ET cycles between natural endogenous hormone cycles and exogenous hormone stimulation cycles. DESIGN: Retrospective cohort analysis. SETTING: Large academic assisted reproductive technology center. PATIENT(S): One thousand three hundred ninety-one patient cycles undergoing frozen-thawed blastocyst-stage ET cycles. MAIN OUTCOME MEASURE(S): Live-birth rate. INTERVENTION(S): The synthetic protocol used GnRH agonist followed by estrogen and P. The natural protocol used monitoring and post-transfer P. RESULT(S): The patients in the two protocols had similar baseline characteristics. Multiple linear regression showed the synthetic protocol to have a higher live-birth rate (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.02-2.09). In patients having two embryos transferred, the synthetic stimulation protocol resulted in a higher live-birth rate per cycle start (32.3% vs. 20.4%; relative risk [RR], 1.58; 95% CI, 1.22-2.06). Similarly, patients with one or two embryos transferred who had additional cryopreserved blastocysts available also had a higher live-birth rate per cycle start (36.1% vs. 12.1; RR, 2.98; 95% CI, 1.16-7.63). CONCLUSION(S): The synthetic hormone protocol was associated with a higher live-birth rate when compared with a natural cycle protocol for frozen-thawed blastocyst-stage ET cycles. This improvement persisted when analysis was controlled for cycle cancellation. The synthetic stimulation protocol for frozen-thawed embryo cycles offers improved outcome results for patients.

Multivariate analysis of factors affecting probability of pregnancy and live birth with in vitro fertilization: an analysis of the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System.

OBJECTIVE: To evaluate factors predictive of clinical pregnancy and of pregnancy loss from assisted reproductive technology (ART) using data from the Society for Assisted Reproductive Technology database for 2004-2006. DESIGN: Retrospective cohort. SETTING: Clinic-based data. PATIENT(S): The study population included 225,889 fresh embryo transfer cycles using autologous oocytes and partner semen. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical intrauterine gestation (presence of gestational sac) and live birth (>or=22 weeks gestation and >or=300 g birth weight). RESULT(S): Increasing maternal age was significantly associated with a reduced odds of conception and increased fetal loss until 19 weeks gestation, but not with later pregnancy loss. Intracytoplasmic sperm injection (ICSI), assisted hatching, and increasing number of embryos transferred had significant positive effects on the odds of conception and pregnancy continuation through the first trimester, but did not affect the risk of later loss. Blacks, Asians, and Hispanics had significantly lower odds of clinical pregnancy compared with whites. Also compared with whites, Hispanics and Asians had a significantly greater risk of pregnancy loss in the second and third trimesters, and blacks had a significantly greater risk of pregnancy loss in all trimesters. CONCLUSION(S): Certain demographic and ART treatment parameters influenced chance of conception and early pregnancy loss, whereas black race and Hispanic ethnicity were also significantly associated with late pregnancy loss in ART-conceived pregnancies.

Logarithmic curves depicting initial level and rise of serum beta human chorionic gonadotropin and live delivery outcomes with in vitro fertilization: an analysis of 6021 pregnancies.

OBJECTIVE: To correlate the live delivery rate with the initial level and rise of serum beta-hCG. DESIGN: Retrospective cohort analysis. SETTING: Large private academic center for assisted reproductive technologies and infertility. PATIENT(S): Records of all patients from 1999 to 2005 undergoing IVF with detectable early serum beta-hCG after ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live delivery rate. RESULT(S): Data from 6021 pregnancies were analyzed. Initial beta-hCG was predictive for delivery rate for all patients and for each age group. After controlling for the first beta-hCG, there were higher loss rates as age increased. Percent rise in second beta-hCG drawn 2 days later added predictive value. A decline in beta-hCG almost always resulted in a failure to deliver. There was a progressive increase in delivery rate as the percent rise in beta-hCG went from 0 to 100%; however, there was no further enhancement in delivery rates beyond the 100% rise point. While a better rise in beta-hCG was a good prognostic factor in all age groups, the differences in outcomes for the different age groups remained, even after controlling for first beta-hCG and percent rise. CONCLUSION(S): Initial level and rise in beta-hCG predicts live delivery rate, with oocyte age providing additional predictive value. The established logarithmic curves should provide convenient reference tools for tracking outcomes and counseling patients.

Live birth sex ratios are not influenced by blastocyst-stage embryo transfer.

OBJECTIVE: To analyze the sex ratio of infants born after blastocyst-stage transfer of embryos with normal preimplantation FISH genetic screening. DESIGN: Retrospective cohort analysis. SETTING: Large academic assisted reproductive technology center. PATIENT(S): Two hundred twenty-eight patients undergoing fresh IVF cycle with blastocyst transfer. INTERVENTION(S): Preimplantation genetic screening for sex complement. MAIN OUTCOME MEASURE(S): Sex ratio in liveborn infants following blastocyst transfer. RESULT(S): One thousand thirteen embryos were normal by preimplantation genetic screening of chromosomes 13, 15, 16, 17, 18, 21, 22, X, and Y. Four hundred ninety-eight normal embryos were transferred to 228 patients with an overall live birth rate of 41.7%. Transferred blastocysts were selected based upon morphologic assessment. When controlling for the sex of the blastocyst embryo, there was no difference in the male-to-female delivery rate per embryo transferred (27.3% vs. 21.4%) (relative risk =1.28, confidence interval 0.93-1.74). Of the live births 51.7% were male and 48.3% were female (P=.61). Subanalysis revealed no difference in male-to-female delivery rates in groups with a 1:1 ratio of male:female embryos transferred, a non 1:1 ratio transferred, or single-sex transfers. CONCLUSION(S): Blastocyst-stage embryo transfer does not influence the live birth sex ratio of embryos with normal preimplantation FISH genetic screening.

The p53 codon 72 single nucleotide polymorphism lacks a significant effect on implantation rate in fresh in vitro fertilization cycles: an analysis of 1,056 patients.

OBJECTIVE: To determine whether the p53 codon 72 single nucleotide polymorphism, a change of the amino acid arginine (Arg) to proline (Pro) resulting from a single nucleotide mutation of guanine (G) to cytosine (C), has a clinically significant effect on implantation rate in fresh IVF cycles. DESIGN: Prospective cohort analysis. SETTING: University-affiliated private IVF center. PATIENT(S): One thousand fifty-six female patients undergoing fresh nondonor IVF cycles. MAIN OUTCOME MEASURE(S): Embryo implantation rate. RESULT(S): Of the 1,056 patients (2,600 total embryos transferred) undergoing their first IVF cycle, 289 had no implantation events and attempted a second cycle. Of the 289 patients in their second cycle, 72 had no implantation events and attempted a third cycle. The p53 codon 72 single nucleotide polymorphism frequencies in the first cycle (homozygous major allele Arg/Arg [G_G] = 45%, heterozygous allele Arg/Pro [G_C] = 44%, and homozygous minor allele Pro/Pro [C_C] = 11%) did not differ significantly across subsequent IVF cycles. There was no statistically significant difference in embryo implantation rate with respect to the single nucleotide polymorphism. CONCLUSION(S): The p53 codon 72 single nucleotide polymorphism lacks a clinically significant effect on embryo implantation rate in patients undergoing fresh nondonor IVF cycles.

A luteal estradiol protocol for anticipated poor-responder patients may improve delivery rates.

OBJECTIVE: To compare IVF data and outcomes between a standard protocol and a luteal phase E(2) protocol. DESIGN: Retrospective cohort analysis. SETTING(S): Large academic assisted reproduction technologies center. PATIENT(S): Fifty-seven infertile patients with a history of poor response to IVF stimulation and 228 matched control patients. INTERVENTION(S): IVF with a standard protocol or a luteal phase E(2) protocol. MAIN OUTCOME MEASURE(S): Live-birth rates. RESULT(S): Patients in the luteal E(2) protocol required more days of stimulation and total gonadotropins and had higher peak E(2) levels when compared with the control group. The luteal E(2) protocol showed a greater percentage of embryos with >or=7 cells on day 3. A trend toward improved delivery rates was seen in the luteal E(2) protocol (28.1% vs. 22.4%; relative risk, 1.25, 0.78-2.03). CONCLUSION(S): A luteal E(2) protocol results in improved day 3 embryo development as demonstrated by the percent of embryos at the >or=7-cell stage. Likewise, the luteal E(2) protocol may ultimately improve pregnancy outcomes for patients with poor response to IVF stimulation.

The predictive value for in vitro fertility delivery rates is greatly impacted by the method used to select the threshold between normal and elevated basal follicle-stimulating hormone.

OBJECTIVE: To evaluate the predictive accuracy of different methodologies for selecting a basal FSH threshold level that prognosticates live birth after IVF. DESIGN: Retrospective. SETTING: Academic private practice. PATIENT(S): Eight thousand nineteen patients who had their basal FSH levels determined by the program's endocrinology laboratory. INTERVENTION(S): Thresholds between normal and elevated basal FSH levels were calculated by using six different methodologies. MAIN OUTCOME MEASURE(S): Live birth rate per initiated IVF cycle. RESULT(S): The thresholds selected by using the manufacturer's normal range or using 95% confidence intervals of a fertile population, the infertile population, or distinct age groups within the infertile population all proved unsatisfactory. The live birth rates for patients in whom there had been a previously elevated FSH level were

Low-dose aspirin use does not improve in vitro fertilization outcomes in poor responders.

OBJECTIVE: To assess if aspirin improves pregnancy outcome in patients undergoing in vitro fertilization (IVF) with a diagnosis of poor response. DESIGN: Retrospective cohort analysis. SETTING: Academic private practice. PATIENT(S): 1250 poor-responder patients undergoing IVF. INTERVENTION(S): Low-dose (81 mg) aspirin before and during an IVF cycle. MAIN OUTCOME MEASURE(S): Live-birth rate. RESULT(S): Patients taking 81 mg of aspirin had statistically significantly higher basal antral follicle counts, more days of stimulation, more ampules of gonadotropins used, higher peak estradiol levels, and more follicles that were > or = 14 mm in diameter on the day of human chorionic gonadotropin administration. There was a decrease in the overall fertilization rate for the patients taking aspirin. There was no difference in IVF outcome rates (implantation, pregnancy, loss, or live birth). CONCLUSION(S): Patients with a diagnosis of poor response who were taking a regimen of 81 of mg aspirin showed an increase in many IVF stimulation parameters and a decrease in fertilization rates. No improvement secondary to 81-mg aspirin intake was found in IVF outcome rates.