An in silico model using prognostic genetic factors for ovarian response in controlled ovarian stimulation: A systematic review.

PURPOSE: To study the use of in silica model to better understand and propose new markers of ovarian response to controlled ovarian stimulation before IVF. METHODS: A systematic review and in silica model using bioinformatics. After the selection of 103 papers from a systematic review process, we performed a GRADE qualification of all included papers for evidence-based quality evaluation. We included 57 genes in the silica model using a functional protein network interaction. Moreover, the construction of protein-protein interaction network was done importing these results to Cytoscape. Therefore, a cluster analysis using MCODE was done, which was exported to a plugin BINGO to determine Gene Ontology. A p value of < 0.05 was considered significant, using a Bonferroni correction test. RESULTS: In silica model was robust, presenting an ovulation-related gene network with 87 nodes (genes) and 348 edges (interactions between the genes). Related to the network centralities, the network has a betweenness mean value = 102.54; closeness mean = 0.007; and degree mean = 8.0. Moreover, the gene with a higher betweenness was PTPN1. Genes with the higher closeness were SRD5A1 and HSD17B3, and the gene with the lowest closeness was GDF9. Finally, the gene with a higher degree value was UBB; this gene participates in the regulation of TP53 activity pathway. CONCLUSIONS: This systematic review demonstrated that we cannot use any genetic marker before controlled ovarian stimulation for IVF. Moreover, in silica model is a useful tool for understanding and finding new markers for an IVF individualization. PROSPERO: CRD42020197185.

Serum anti-Müllerian hormone levels are negatively related to Follicular Output RaTe (FORT) in normo-cycling women undergoing controlled ovarian hyperstimulation.

BACKGROUND: Since in rodents anti-Müllerian hormone (AMH) has been shown to inhibit antral follicle responsiveness to FSH, we aimed at verifying whether a relationship exists between serum AMH levels and antral follicle responsiveness to exogenous FSH in normo-cycling women. METHODS: Serum AMH, estradiol (E(2)) and FSH levels were prospectively measured on cycle day 3 in patients undergoing controlled ovarian hyperstimulation (COH) with a time-release GnRH agonist and standardized FSH doses. In 162 patients, follicles were counted after pituitary suppression and before FSH administration (baseline; small antral follicles; 3-8 mm), and on the day of hCG (dhCG; pre-ovulatory follicles; 16-22 mm). Antral follicle responsiveness to FSH was estimated by the Follicular Output RaTe (FORT), determined by the ratio pre-ovulatory follicle count on dhCG × 100/small antral follicle count at baseline. RESULTS: Serum AMH levels were positively correlated with the number of small antral follicles at baseline (r = 0.59; P < 0.0001) and pre-ovulatory follicles on dhCG (r = 0.17; P < 0.04). Overall, FORT was 47.5 ± 1.4% and failed to be influenced by the woman's age, BMI or basal E(2) and FSH level. Conversely, multiple regression analysis showed that FORT was negatively correlated with AMH levels (r = -0.30; P < 0.001), irrespective of duration of COH and total FSH dose. CONCLUSIONS: The percentage of follicles that effectively respond to FSH by reaching pre-ovulatory maturation is negatively and independently related to serum AMH levels. Although the mechanisms underlying this finding remain unclear, it is in keeping with the hypothesis that AMH inhibits follicle sensitivity to FSH.

Follicular-fluid anti-Müllerian hormone concentration is similar in patients with endometriosis compared with non-endometriotic patients.

This cross-sectional prospective study assessed follicular-fluid anti-Müllerian hormone (AMH) concentrations in infertile patients with mild/minimal endometriosis during natural IVF. Thirty-two women participated in the study. Patients were divided into two groups: tubal obstruction without endometriosis (control group) and minimal/mild endometriosis (study group). All patients underwent laparoscopy for assessment of infertility; at the same time, any foci of endometriosis found were cauterized. AMH concentration was measured in the follicular fluid of a single follicle when it achieved pre-ovulatory maturation by ultrasensitive enzyme-linked immunosorbent assay. Likewise, AMH, FSH and inhibin B content in serum was also measured. Age (30 ± 1.3 and 32 ± 0.8 years) and body mass index (22 ± 0.6 and 22 ± 0.5 kg/m(2)), day-3 antral follicle count (11.3 ± 1.7 and 10.7 ± 1.5), serum FSH concentrations (5.4 ± 0.6 and 5.0 ± 0.3 IU/ml) and follicular-fluid AMH concentrations (1.8 ± 0.3 and 1.5 ± 0.1 ng/ml, study and control group, respectively; mean difference 0.33, 95% CI -0.21 to 0.88) were similar in both groups. This study shows that infertile patients with minimal/mild endometriosis have a similar concentration of AMH in the follicular fluid after natural IVF as compared with control subjects.

Variability of endometrial glandular opening count in infertile patients prior to first IVF treatment.

The aim of the present study was to evaluate the number of endometrial glandular openings, using previously reported software that provides an objective count, and to assess the variability of this parameter during the luteal phase in a population of women who had no hormonal abnormalities presenting with tubal infertility or male factor infertility. A cross-sectional study was performed comprising 561 patients selected for a diagnostic hysteroscopy for the investigation of infertility. Hysteroscopy was performed during the mid-secretory phase prior to the first IVF treatment cycle. A total of 561 image frames from all patients were analysed. All images were automatically selected by the software, which also evaluated the number of endometrial glandular openings. The mean +/- SD glandular opening count was 53.2 +/- 30 (range 4-158). The analysis of variation showed a significant difference (P = 0.001) among all video frames. In conclusion, endometrial glandular opening count, as measured by the method described, can be used in investigations during the luteal phase. Although a lack of pattern was observed in endometrial maturation, this feature should be explored further in this subgroup of patients.

[The influence of exogenous LH/hCG activity on serum progesterone levels on the day of hCG administration in in vitro fertilization]. / Influence de l'activité LH/hCG exogène sur le taux sérique de progestérone le jour de l'hCG en fécondation in vitro.

OBJECTIVES: Clarifying whether the addition of recombinant LH (rLH) to recombinant FSH (rFSH) leads to progesterone (P4) levels on dhCG comparable to those obtained with stimulation with FSH and hCG (HP-hMG) MATERIALS AND METHODS: Pituitary-desensitized patients, matched for age and follicle reserve, received rFSH+LH (n=729) or HP-hMG (n=729). In the rFSH+rLH group, rLH (75 UI/day) was started at day 6. To control for the influence of ovarian response on P4, we divided serum P4 levels by the number of growing follicles (13-22 mm; "per follicle" P4 levels) and performed a multivariate analysis. RESULTS: Serum P4 levels on dHCG were lower in the HP-hMG (median: 0.63 ng/mL, max-min: 0.10-2.97) than in the rFSH+rLH group (0.91 ng/mL; 0.10-4.65, P<0.0001), as well as "per-follicle" P4 levels (0.055 ng/mL/growing follicle, 0.006-0.284 vs 0.077 ng/mL/growing follicle, 0.003-0.336; P<0.0001). CONCLUSIONS: HP-hMG led to lower P4 levels on day hCG than rFSH+rLH irrespective of the intensity of the ovarian response and the adjunction of rLH (75 IU/day from day 6 onward).

Luteal phase oestradiol administration in ovarian stimulation cycles with GnRH antagonist is comparable to the GnRH agonist (long) protocol.

PURPOSE: The purpose of the study was to compare the effectiveness of GnRH antagonist with luteal phase estradiol administration to GnRH agonist cycles, long protocol. METHODS: 55 IVF-ICSI patients received oestradiol in the luteal phase of the cycle, before a cycle with GnRH antagonist. Fifty-five patients submitted to IVF-ICSI with the use of agonist were allocated, age matched, as a control group (historical control). The primary outcome was the number of retrieved oocytes. RESULTS: Patients were similar in terms of clinical characteristics. No differences were found in the number of oocytes retrieved (study group, 8.1 +/- 4.7; control group, 7.4 +/- 4.5) or in oocyte quality. CONCLUSIONS: We clearly demonstrated that the effectiveness of GnRH antagonist when combined with luteal phase estradiol is comparable to GnRH agonist cycles.