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.

Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome.

BACKGROUND: Looking for a qualitative marker of ovarian function, we aimed to verify whether responsiveness of antral follicles to FSH administration, as reflected by the Follicular Output RaTe (FORT), is related to their reproductive competence. METHODS: We studied 322 IVF-ET candidates aged 25-43 years who underwent controlled ovarian hyperstimulation with similar initial FSH doses. Antral follicle (3-8 mm) count (AFC) and pre-ovulatory follicle (16-22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (<42%; n= 102), average (42-58%; n= 123) and high (>58%; n= 97). RESULTS: The average FORT was 50.6% (range, 16.7-100.0%). Clinical pregnancy rates per oocyte retrieval increased progressively from the low to the high FORT groups (33.3, 51.2 and 55.7%, respectively, P< 0.003) and such a relationship assessed by logistic regression was independent of the confounding covariates, women's ages, AFC and PFC. CONCLUSIONS: The observed relationship between IVF-ET outcome and the percentage of antral follicles that effectively respond to FSH administration reaching pre-ovulatory maturation suggests that FORT may be a qualitative reflector of ovarian follicular competence. Further studies with broader inclusion criteria and more personalized protocols are needed to validate these results.

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).

[Intra-uterine insemination outcomes according to the serum AMH level on day 3]. / Valeur prédictive de l'hormone antimüllérienne sur les issues des inséminations intra-utérines.

UNLABELLED: The aim of this retrospective study was to compare the IUI outcomes according to serum antiMullerian hormone (AMH) levels on day 3 of cycle. PATIENTS AND METHOD: Three hundred and sixteen patients undergoing their first IUI cycle after a serum AMH level test in our laboratory. These patients were less than 39 years of age and the number of motile spermatozoa inseminated (NMSI) was superior or equal to five millions. Patients were divided in three groups according to their serum AMH level: the group 1 with AMH level less than 1ng/ml, the group 2 with AMH level between 1 and 4.5ng/ml, and the group 3 with AMH level greater than 4.5ng/ml. MAIN OUTCOMES MEASURE(S): clinical pregnancy rate and ongoing pregnancy rate per IUI cycle. RESULT(S): No statistical difference has been observed on follicle stimulation, number of mature follicle, oestradiol level on day hCG, clinical pregnancy rate, spontaneous abortion. The ongoing pregnancy rate per IUI practised were respectively: 15.5% for AMH inferior to 1ng/ml versus 15.2% for AMH between 1 to 4.5ng/ml and versus 13.6% for AMH superior to 4.5ng/ml. CONCLUSION(S): AMH value does not seem to have an impact on the IUI outcomes and particularly on the pregnancy rates.

[Serum AMH level is not a predictive value for IVF in modified natural cycle: analysis of 342 cycles]. / L'AMH sérique n'a pas de valeur prédictive en fécondation in vitro en cycle naturel modifié : analyse de 342 cycles.

The objective is to compare the IVF procedures in modified natural cycle outcomes according to serum anti-Mullerian hormone (AMH) levels. We included in this retrospective study 342 patients undergoing their first IVF in modified natural cycle. Patients were regrouped in three groups according to their serum AMH level: group 1 was defined by patients with AMH level<0.97 ng/mL (<25th percentile), group 2, patients with AMH level between 0.97 ng/mL and 2.60 ng/mL (25-75th percentile), and group 3, patients with AMH level between 2.61 ng/mL and 6.99 ng/mL (>75th percentile). The main outcomes were cancellation rate, embryo transfer rate and clinical pregnancy rate, ongoing pregnancy rate and implantation rate. No difference has been observed on cancellation rate, embryo transfer rate, clinical pregnancy rate and implantation rate. The ongoing pregnancy rate per IVF cycle was respectively: 12.8±3.6% for AMH inferior to 0.97 ng/mL versus 12.5±2.5% for AMH between 0.97 to 2.60 ng/mL and 13.4±4.2% for AMH between 2.61 ng/mL and 6.99 ng/mL. In conclusion, IVF in modified natural cycles procedures should be considered as an option for patients with an altered ovarian reserve defined by a serum AMH inferior to 1 ng/mL. Serum AMH level seems a quantitative marker of the ovary but not a quality factor. Serum AMH level does not seem to be a prognostic factor for ongoing pregnancy rated in IVF modified cycles.

Peritoneal and serum interleukin-18 levels are not increased in women with minimum or mild endometriosis.

Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 family. Endometriosis is strongly associated with sub-fertility, and affects about 15% of women of reproductive age. IL-18 may favor the progression of endometriosis. The objective of the present study was to determine the concentration of IL-18 in the serum and peritoneal fluid of infertile women with endometriosis. Forty infertile and 25 fertile women were screened in a teaching hospital. Thirty-four infertile patients with minimal or mild endometriosis and 22 fertile controls were enrolled in the study. The primary outcome was the estimate of IL-18 levels and the secondary outcome was the correlation between serum and peritoneal levels of IL-18. There were no differences between the two groups regarding age, body mass index and levels of peritoneal fluid IL-18 (mean +/- SD): 290.85 +/- 173.02 pg/mL for infertile women vs 374.21 +/- 330.15 pg/mL for controls; or serum IL-18: 391.07 +/- 119.71 pg/mL for infertile women vs 373.42 +/- 129.11 pg/mL for controls. However, a positive association was found between serum and peritoneal IL-18 levels in patients with endometriosis: r = 0.794, P = 0.0001. All measurements were carried out at the same time by the Human IL-18 Immuno Assay ELISA kit (MBL Co. Ltd., Japan). The present study did not find evidence supporting the hypothesis that IL-18 levels are associated with infertility in women with minimal and mild endometriosis, although a positive correlation was detected in these women between peritoneal and serum levels of IL-18.

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.

Diabetic retinopathy in a population of 1,302 insulin dependent diabetics (IDDM) diagnosed before 30 years of age.

The authors analyse the data resulting from the first ophthalmological observation of 1,302 insulin dependent diabetics whose age at diagnosis is less than 30 years and who have been observed regularly by the Portuguese Diabetic Association. The prevalence of retinopathy is 41, 6%; 34.3% is non-proliferative and 7.3% is proliferative. Retinopathy is more frequent in males (P < 0.001). The prevalence of retinopathy increases with the duration of diabetes and it is equal to or greater than 80% in people who have had diabetes for 10 years or more. 'Poor' glucose control, the coexistence of other late complications and arterial hypertension increase the risk of retinopathy (P < 0.001).

Peritoneal and serum interleukin-18 levels are not increased in women with minimum or mild endometriosis

Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 family. Endometriosis is strongly associated with sub-fertility, and affects about 15 percent of women of reproductive age. IL-18 may favor the progression of endometriosis. The objective of the present study was to determine the concentration of IL-18 in the serum and peritoneal fluid of infertile women with endometriosis. Forty infertile and 25 fertile women were screened in a teaching hospital. Thirty-four infertile patients with minimal or mild endometriosis and 22 fertile controls were enrolled in the study. The primary outcome was the estimate of IL-18 levels and the secondary outcome was the correlation between serum and peritoneal levels of IL-18. There were no differences between the two groups regarding age, body mass index and levels of peritoneal fluid IL-18 (mean ± SD): 290.85 ± 173.02 pg/mL for infertile women vs 374.21 ± 330.15 pg/mL for controls; or serum IL-18: 391.07 ± 119.71 pg/mL for infertile women vs 373.42 ± 129.11 pg/mL for controls. However, a positive association was found between serum and peritoneal IL-18 levels in patients with endometriosis: r = 0.794, P = 0.0001. All measurements were carried out at the same time by the Human IL-18 Immuno Assay ELISA kit (MBL Co. Ltd., Japan). The present study did not find evidence supporting the hypothesis that IL-18 levels are associated with infertility in women with minimal and mild endometriosis, although a positive correlation was detected in these women between peritoneal and serum levels of IL-18.