Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols

Variability in the subfertile patient population excludes the possibility of a single approach to controlled ovarian stimulation (COS) covering all the requirements of a patient. Modern technology has led to the development of new drugs, treatment options and quantitative methods that can identify single patient characteristics. These could potentially be used to match patients with the right treatment options to optimise efficacy, safety and tolerability during COS. Currently, age and follicle-stimulating hormone (FSH) level remain the most commonly used single patient characteristics in clinical practice. These variables only provide a basic prognosis for success and indications for standard COS treatment based on gross patient categorisation. In contrast, the anti-Müllerian hormone level appears to be an accurate predictor of ovarian reserve and response to COS, and could be used successfully to guide COS. The antral follicle count is a functional biomarker that could be useful in determining the dose of FSH necessary during stimulation and the success of treatment. Finally, in the future, genetic screening may allow an individual patient's response to stimulation during COS to be predicted based on genotype. Unfortunately, despite the predictive power of these measures, no single biomarker can stand alone as a guide to determine the best treatment option. In the future, hormonal, functional and genetic biomarkers will be used together to personalise COS

Relationship between a uterine fibroid diagnosis and the risk of adverse obstetrical outcomes:a cohort study

ObjectiveThe aim was to investigate the association between clinically significant uterine fibroids and preterm birth, caesarean section (CS), postpartum haemorrhage (PPH), placental abruption, intrauterine growth restriction (IUGR) and uterine rupture.Methods, participants and settingA historical cohort study based on data from the Danish National Birth Cohort, the Danish National Patient Registry and the Danish National Birth Registry (DNBR). The final study population consisted of 92 696 pregnancies and was divided into four groups for comparison. Group 1: pregnancies of women without a fibroid diagnosis code or fibroid operation code; group 2: pregnancies of women with a fibroid diagnosis code before pregnancy, during pregnancy or up to 1 year after delivery, and no fibroid operation code before pregnancy; group 3: pregnancies of women with a fibroid diagnosis code given more than 1 year after delivery; and group 4: pregnancies of women with a fibroid operation code given before pregnancy.ResultsA diagnosis of fibroids before pregnancy yielded an increased risk of preterm birth (gestational age (GA) ≤37 weeks) (OR 2.27 (1.30─3.96)) and extreme preterm birth (GA 22+0─27+6 weeks, OR 20.09 (8.04─50.22)). The risk of CS was increased (OR 1.83 (1.23─2.72)) for women with a fibroid diagnosis code given before pregnancy; significantly increased risk of elective CS (OR 1.92 (1.11─3.32)), but not acute CS (OR 1.54 (0.94─2.52)). The risks of PPH, placental abruption or IUGR were not increased in any of the groups.ConclusionWe found a strong association between clinically significant uterine fibroids and preterm birth, and an association between clinically significant uterine fibroids and CS. In contrast, no association between clinically significant uterine fibroids and PPH, placental abruption or IUGR was seen

GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles—A Systematic PRISMA Review and Meta-analysis

IntroductionThe use of GnRH agonist (GnRHa) for final oocyte maturation trigger in oocyte donation and elective frozen embryo transfer cycles is well established due to lower ovarian hyperstimulation syndrome (OHSS) rates as compared to hCG trigger. A recent Cochrane meta-analysis concluded that GnRHa trigger was associated with reduced live birth rates (LBRs) in fresh autologous IVF cycles compared to hCG trigger. However, the evidence is not unequivocal, and recent trials have found encouraging reproductive outcomes among couples undergoing GnRHa trigger and individualized luteal LH activity support. Thus, the aim was to compare GnRHa trigger followed by luteal LH activity support with hCG trigger in IVF patients undergoing fresh embryo transfer.Material and methodsWe conducted a systematic review and meta-analysis of randomized trials published until December 14, 2016. The population was infertile patients submitted to IVF/ICSI cycles with GnRH antagonist cotreatment who underwent fresh embryo transfer. The intervention was GnRHa trigger followed by LH activity luteal phase support (LPS). The comparator was hCG trigger followed by a standard LPS. The critical outcome measures were LBR and OHSS rate. The secondary outcome measures were number of oocytes retrieved, clinical and ongoing pregnancy rates, and miscarriage rates.ResultsA total of five studies met the selection criteria comprising a total of 859 patients. The LBR was not significantly different between the GnRHa and hCG trigger groups (OR 0.84, 95% CI 0.62, 1.14). OHSS was reported in a total of 4/413 cases in the GnRHa group compared to 7/413 in the hCG group (OR 0.48, 95% CI 0.15, 1.60). We observed a slight, but non-significant increase in miscarriage rate in the GnRHa triggered group compared to the hCG group (OR 1.85; 95% CI 0.97, 3.54).ConclusionGnRHa trigger with LH activity LPS resulted in comparable LBRs compared to hCG trigger. The most recent trials reported LBRs close to unity indicating that individualization of the LH activity LPS improved the luteal phase deficiency reported in the first GnRHa trigger studies. However, LPS optimization is needed to further limit OHSS in the subgroup of normoresponder patients (<14 follicles ≥ 11 mm).Prospero registration numberCRD4201605109

Aromatase inhibitors in stimulated IVF cycles

Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol level

Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome:a retrospective cohort study

BACKGROUND: Conventional luteal support packages are inadequate to facilitate a fresh transfer after GnRH agonist (GnRHa) trigger in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). By providing intensive luteal-phase support with oestradiol and progesterone satisfactory implantation rates can be sustained. The objective of this study was to assess the live-birth rate and incidence of OHSS after GnRHa trigger and intensive luteal steroid support compared to traditional hCG trigger and conventional luteal support in OHSS high risk Asian patients. METHODS: We conducted a retrospective cohort study of 363 women exposed to GnRHa triggering with intensive luteal support compared with 257 women exposed to conventional hCG triggering. Women at risk of OHSS were defined by ovarian response ≥15 follicles ≥12 mm on the day of the trigger. RESULTS: Live-birth rates were similar in both groups GnRHa vs hCG; 29.8% vs 29.2% (p = 0.69). One late onset severe OHSS case was observed in the GnRHa trigger group (0.3%) compared to 18 cases (7%) after hCG trigger. CONCLUSIONS: GnRHa trigger combined with intensive luteal steroid support in this group of OHSS high risk Asian patients can facilitate fresh embryo transfer, however, in contrast to previous reports the occurrence of late onset OHSS was not completely eliminated

New algorithm for OHSS prevention

Ovarian hyperstimulation syndrome (OHSS) still remains a life-threatening complication of in vitro fertilization treatment (IVF), keeping patients and especially those, who previously experienced OHSS, from attempting infertility treatment and childbearing. The recent implementation of four new modalities: the GnRH antagonist protocol, GnRH agonist (GnRHa) triggering of ovulation, blastocyst transfer and embryo/oocyte vitrification, renders feasible the elimination of OHSS in connection with ovarian hyperstimulation for IVF treatment. The proposed current algorithm is based on the number of follicles developed after ovarian stimulation, setting a cut-off level at the development of 18 or more follicles. Further, fulfilling this criterion, the algorithm is based on four decision-making points: the final day of patient work-up, the day of triggering final oocyte maturation, day-1 post oocyte pick-up (OPU) and day-5 post OPU

Mid-Luteal 17-OH Progesterone Levels in 614 Women Undergoing IVF-Treatment and Fresh Embryo Transfer—Daytime Variation and Impact on Live Birth Rates

Introduction: Corpus luteum (CL) produces progesterone (P4) and 17-OH progesterone (17-OH P4) during the luteal phase. Contrary to P4, 17-OH P4 is not supplied as part of the luteal phase support following IVF-treatment. Therefore, measuring endogenous serum 17-OH P4 levels may more accurately reflect the CL function compared to monitoring serum P4 concentrations.Objective: To explore the correlation between mid-luteal serum 17-OH P4 levels and live birth rates and to explore the possible daytime variations in mid-luteal serum 17-OH P4.Design: Prospective cohort study.Patients: 614 women undergoing IVF-treatment and fresh embryo transfer.Intervention: All patients had serum 17-OH P4 measured 7 days after oocyte pick-up (OPU+7). Furthermore, on OPU+7, seven patients underwent repeated blood sampling during daytime to clarify the endogenous daytime secretory pattern of 17-OH P4.Outcome measure: Live birth rate.Secondary outcome measure: Daytime variation in serum 17-OH P4 levels.Results: The highest chance of a live birth was seen with mid-luteal 17-OH P4 between 6.0 and 14.0 nmol/l. The chance of a live birth was reduced below (RD −10%, p = 0.07), but also above the optimal range for 17-OH P4 (RD −12%, p = 0.04). Patients with diminished CL-function (17-OH P4 < 6 nmol/l) displayed clinically stable 17-OH P4 values, whereas patients with 17-OH P4 levels >6 nmol/l showed random 17-OH P4 fluctuations during daytime.Conclusion: The association between 17-OH P4 and reproductive outcomes is non-linear, and the negative effect of excessive CL-secretion seems to be just as strong as the negative effect of a reduced CL-function during the peri-implantation period